23 June 2016
EMA/CHMP/668339/2015
Committee for Medicinal Products for Human Use (CHMP)
Extension of indication variation assessment report
Invented name: Cervarix
International non-proprietary name: human papillomavirus vaccine [types
16, 18] (recombinant, adjuvanted, adsorbed)
Procedure No. EMEA/H/C/000721/II/0067
Marketing authorisation holder (MAH): GlaxoSmithKline Biologicals
Note
Variation assessment report as adopted by the CHMP with all information of a commercially
confidential nature deleted.
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© European Medicines Agency, 2016. Reproduction is authorised provided the source is acknowledged.
Table of contents
1. Background information on the procedure .............................................. 4
1.1. Type II variation .................................................................................................. 4
1.2. Steps taken for the assessment of the product ......................................................... 4
2. Scientific discussion ................................................................................ 6
2.1. Introduction......................................................................................................... 6
2.2. Non-clinical aspects .............................................................................................. 7
2.3. Clinical aspects .................................................................................................... 8
2.3.1. Introduction ...................................................................................................... 8
2.4. Clinical efficacy .................................................................................................. 10
2.4.1. Main studies ................................................................................................... 10
2.4.2. Discussion on clinical efficacy ............................................................................ 34
2.4.3. Conclusions on the clinical efficacy ..................................................................... 37
2.5. Clinical safety .................................................................................................... 38
2.5.1. Discussion on clinical safety .............................................................................. 43
2.5.2. Conclusions on clinical safety ............................................................................ 45
2.5.3. PSUR cycle ..................................................................................................... 46
2.6. Risk management plan........................................................................................ 46
2.7. Update of the Product information ........................................................................ 49
2.7.1. User consultation ............................................................................................. 49
3. Benefit-Risk Balance.............................................................................. 50
4. Recommendations ................................................................................. 53
5. EPAR changes ........................................................................................ 53
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List of abbreviations
AE Adverse Event
AIN Anal Intraepithelial Neoplasia
ATP According to Protocol
CHMP Committee for Medicinal Products for Human Use
CI Confidence Interval
CIN Cervical Intraepithelial Neoplasia
CSR Clinical Study Report
CVT Costa Rica HPV Vaccine Trial
DLP Data Lock Point
DNA DeoxyriboNucleic Acid
ED50 Estimated Dose = serum dilution giving a 50% reduction of the signal compared to a control
without serum
ELISA Enzyme-Linked Immunosorbent Assay
EMA European Medicines Agency
GCP Good Clinical Practice
GMT Geometric Mean Titre
GSK GlaxoSmithKline
HBs Ag Hepatitis B surface Antigen
HPV Human Papillomavirus
MPL 3-O-desacyl-4'-mono-phosphoryl-lipid
MSC Medically significant conditions
MSM Men having sex with men
NCI National Cancer Institute
NOAD New Onset Autoimmune Disease
NOCD New Onset Chronic Disease
PBNA Pseudovirion-Based Neutralisation Assay
PBRER Periodic Benefit Risk Evaluation Report
PCR Polymerase Chain Reaction
PI Product Information
PSUR Periodic Safety Update Report
qHPV quadrivalent human papillomavirus vaccine (Gardasil/Silgard)
SAE Serious Adverse Event
SmPC Summary of Product Characteristics
TVC Total Vaccinated Cohort
VCSP Vaccines Clinical Safety and Pharmacovigilance
VLP Virus-like Particle
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1. Background information on the procedure
1.1. Type II variation
Pursuant to Article 16 of Commission Regulation (EC) No 1234/2008, GlaxoSmithKline Biologicals
submitted to the European Medicines Agency on 12 March 2015 an application for a variation.
The following variation was requested:
Variation requested
Type
C.I.6.a
Type II
Annexes
affected
C.I.6.a - Change(s) to therapeutic indication(s) - Addition
I and IIIB
of a new therapeutic indication or modification of an
approved one
Extension of Indication to include prevention against premalignant anal lesions and anal cancer as of 9
years of age for Cervarix; as a consequence, sections 4.1, 4.8 and 5.1 of the SmPC are updated. The
Package Leaflet is updated in accordance. In addition, the Marketing authorisation holder (MAH) took
the opportunity to update the RMP (v.11.0) including the new indication.
The requested variation proposed amendments to the Summary of Product Characteristics and
Package Leaflet and to the Risk Management Plan (RMP).
Information on paediatric requirements
Pursuant to Article 8 of Regulation (EC) No 1901/2006, the application included an EMA Decision
(P/0008/2015) on the granting of a (product-specific) waiver.
Information relating to orphan market exclusivity
Similarity
Pursuant to Article 8 of Regulation (EC) No. 141/2000 and Article 3 of Commission Regulation (EC) No
847/2000, the MAH did not submit a critical report addressing the possible similarity with authorised
orphan medicinal products because there is no authorised orphan medicinal product for a condition
related to the proposed indication.
Scientific advice
The MAH did not seek Scientific Advice at the CHMP.
1.2. Steps taken for the assessment of the product
The Rapporteur and Co-Rapporteur appointed by the CHMP were:
CHMP Rapporteur:
Daniel Brasseur
PRAC Rapporteur:
Jean-Michel Dogné
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CHMP Co-Rapporteur:
N/A
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Timetable
Actual dates
Submission date
12 March 2015
Start of procedure
28 March 2015
CHMP Rapporteur’s preliminary assessment report circulated on
26 May 2015
PRAC Rapporteur’s preliminary assessment report circulated on
26 May 2015
PRAC Rapporteur’s updated assessment report circulated on
5 June 2015
PRAC RMP advice and assessment overview adopted by PRAC
11 June 2015
CHMP Rapporteur’s updated assessment report circulated on
18 June 2015
Request for supplementary information and extension of timetable adopted
25 June 2015
by the CHMP on
MAH’s responses submitted to the CHMP on
15 September 2015
CHMP Rapporteur’s preliminary assessment report on the MAH’s responses
29 October 2015
circulated on
PRAC Rapporteur’s preliminary assessment report on the MAH’s responses
29 October 2015
circulated on
PRAC RMP advice and assessment overview adopted by PRAC
6 November 2015
CHMP Rapporteur’s updated assessment report on the MAH’s responses
16 November 2015
circulated on
2nd request for supplementary information and extension of timetable
19 November 2015
adopted by the CHMP on
MAH’s responses submitted to the CHMP on
28 January 2016
CHMP Rapporteur’s preliminary assessment report on the MAH’s responses
2 March 2016
circulated on
PRAC Rapporteur’s preliminary assessment report on the MAH’s responses
2 March 2016
circulated on
PRAC RMP advice and assessment overview adopted by PRAC
3
rd
request for supplementary information and extension of timetable
17 March 2016
1 April 2016
adopted by the CHMP on
MAH’s responses submitted to the CHMP on
24 May 2016
PRAC Rapporteur’s preliminary assessment report on the MAH’s responses
30 May 2016
circulated on
CHMP Rapporteur’s preliminary assessment report on the MAH’s responses
31 May 2016
circulated on
PRAC RMP advice and assessment overview adopted by PRAC
9 June 2016
CHMP opinion
23 June 2016
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2. Scientific discussion
2.1. Introduction
The product
Cervarix is a HPV vaccine that contains recombinant C-terminally truncated major capsid L1 proteins of
HPV types 16 and 18 as active ingredients. The L1 proteins of HPV-16 and HPV-18 are separately
produced using a recombinant Baculovirus expression system. After expression of the L1 proteins and
further purification, the L1 proteins assembled separately as virus-like particles (VLP). The VLPs of
each HPV type are formulated with the AS04 adjuvant system composed of aluminium hydroxide and
3-O-desacyl-4-monophosphoryl lipid A (MPL). The MPL immunostimulant is a detoxified derivative of
the lipopolysaccharide of the gram negative bacterium Salmonella minnesota R595 strain. One dose of
Cervarix contains 20μg of HPV-16 L1 and 20μg of HPV-18 L1 proteins adjuvanted with AS04 and is
presented as a sterile turbid liquid suspension for injection, filled as a 0.5ml monodose in either
syringes or vials.
Cervarix was first registered in 2007 in Australia and the vaccine is currently licensed for use in more
than 130 countries worldwide. In the European Union, Cervarix is indicated from 9 years of age
onwards for the prevention of premalignant genital (cervical, vulvar and vaginal) lesions and cervical
cancer causally related to certain oncogenic Human Papillomavirus (HPV) types. The vaccination
schedule depends on the age of the subject. From 9 to and including 14 years, the vaccine is given as
two doses, the second dose given between 5 and 13 months after the first dose. From 15 years and
above, the vaccine is given as three doses at 0, 1, 6 months.
No Paediatric Investigational Plan (PIP) has been agreed for Cervarix. In 2008 a full-waiver was
granted for “Infection by Human Papillomavirus in females”. In 2014 a waiver was submitted for all
subsets of the paediatric male population for Human Papillomavirus type 18 L1 protein / Human
Papillomavirus type 16 L1 protein (Cervarix) for the “Prevention of infection by human papillomavirus
in males”. The Paediatric Committee (PDCO) granted a waiver on the grounds that the specific
medicinal product does not represent a significant therapeutic benefit as the needs are already covered
by other approved HPV vaccines.
Problem statement
Anal HPV types 16 and 18 infection and anal cancer
Efficacy of prevention against high grade cervical lesions has been clinically demonstrated for both
Cervarix and qHPV. As for cervical cancers, anal cancers are also associated with oncogenic HPV type
infection. The anal canal is covered with epithelium similar to that covering the cervix. Analogous to
the cervical transformation zone, the anal canal has a transformation zone, where columnar cells of
the rectum meet squamous cells of the anus. HPV infection and the pathogenic process of disease
development occur in a similar way in the anal canal as in the cervical canal (Alani, 1998; Hernandez,
2005). In the same way as cervical cancer is preceded by cervical intraepithelial neoplasia (CIN), HPVrelated anal cancer is preceded by anal intraepithelial neoplasia (AIN) lesions, classified in grades 1 to
3 (Watson, 2006, Abbasakoor, 2005). HPV-related anal cancer is predominantly associated with
infection with HPV types 16 and 18 (Chaturvedi, 2010), that are included in Cervarix. It is estimated
that up to 90% of all anal cancers are caused by HPV-16 and HPV-18 (WHO, 2014) and HPV-16 and
HPV-18 are responsible for approximately 78% of HPV-related high-grade anal (AIN 2/3) intraepithelial
neoplasia (De Vuyst, 2009). In a large population-based case-controlled study conducted in both men
and women in the US, 88% of all anal tumours were HPV DNA positive, with HPV-16 the most frequent
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type found in the tissues (73% of all tumours), followed by HPV-18 (6.9%), regardless of gender. In
the case of men who were not exclusively heterosexual, the proportion of HPV DNA positive anal
tumours raised to 97.7% (Daling, 2004). A study conducted in France showed HPV-16 and HPV-18
infection (alone or in association with other HPV types) in 78% of all anal cancer cases (Abramowitz,
2011). The strong association between HPV infection, in particular of HPV types 16 and 18 and anal
cancer is confirmed through two meta-analyses, with HPV DNA detected in 71% of invasive anal
cancers (of which 72% were associated with HPV-16/18) in the first analysis (Hoots, 2009) and HPV
prevalence of 84.3% in anal carcinoma in the second analysis (De Vuyst, 2009) of which 73.4%
related to HPV-16, followed by HPV- 18 (5.2%). In the analysis of the placebo arm of a multi country
clinical trial with qHPV, anogenital acquisition of HPV-6/11/16/18 was common among heterosexual
males, with 9.0 cases per 100 person/years at risk observed and HPV-16 was the type found with the
highest incidence (Moreira, 2014). Among HIV-1-negative men having sex with men (MSM) attending
a clinic in Italy, 74.8% were DNA positive for any HPV type and 56.2% were positive for any oncogenic
HPV type. The most common oncogenic HPV type was HPV-16 (17.8% of HPV-positive subjects)
(Donà, 2012). In healthy young females enrolled in the Costa Rica HPV Vaccine Trial (CVT), also
referred to as study HPV-009 (conducted by NCI in collaboration with GSK), overall anal HPV infection
prevalence was 31.6%, with higher prevalence in women with history of anal intercourse (43.4% vs.
28.4% for women without history) (Castro, 2012). These observations demonstrate that HPV infection
is common among women and men (both heterosexual and MSM).
Mode of action of HPV vaccines
The prevention by vaccination against premalignant genital lesions and cervical cancer is mediated by
the subjects immune system eliciting antibodies against the VLPs present in the vaccine. No serological
correlate of protection has been established for HPV vaccines, however high levels of antibodies
against HPV-16/18 are indicative of an effective protection against HPV infection (Stanley, 2012;
Safaeian, 2010; Romanowski, 2009; Castellsagué, 2014). The neutralising antibodies will prevent the
entry of the virus into the basal epithelial cells, thereby preventing initial infection of the individual
with the pathogen (Schiller, 2010; Day, 2010). Likewise, vaccination may also protect against infection
of the anal basal epithelial cells with HPV types 16 and 18, thereby preventing the first step in the
pathogenic development of anal cancer. Vaccination with qHPV has indeed been shown to be
efficacious in preventing the development of pre-cancerous anal lesions in a clinical trial (Palefsky,
2011).
Current application
The purpose of this variation was to propose an extension of the therapeutic indication of Cervarix to
include prevention against premalignant anal lesions and anal cancer in males and females aged 9
years and older, based on immunogenicity and safety data obtained from 4 clinical studies that were
either completed (HPV-010, HPV-011) or ongoing at the time of the initial submission with interim data
submitted (HPV-040, HPV-071). No efficacy data were generated as part of these studies.
2.2. Non-clinical aspects
No new clinical data have been submitted in this application, which was considered acceptable by the
CHMP.
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2.3. Clinical aspects
2.3.1. Introduction
GCP
The Clinical trials were performed in accordance with GCP as claimed by the MAH.
The MAH has provided a statement to the effect that clinical trials conducted outside the community
were carried out in accordance with the ethical standards of Directive 2001/20/EC.
•
Tabular overview of clinical studies
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2.4. Clinical efficacy
No efficacy data were generated as part of the studies HPV 010, HPV-011, HPV-040 (month 7) and
HPV-071.
The MAH proposes to justify the potential clinical efficacy of Cervarix against anal lesions and anal
cancer in both males and females by:
•
In females: Immunogenicity bridging to another HPV vaccine that currently has the “anal”
indication based on efficacy data in males (qHPV);
•
In males: Immunogenicity bridging to a population in which vaccine efficacy in the “cervical”
indication has been demonstrated (females aged 15-25 years).
Table 1. Overview of immunobridging to support the anal indication application
Gender
Age
(years)
Comparison
Data
point
Cervarix
3-dose
M
F
10-18
Seroresponses rate, GMT
M7
●
12-15
GMT
M7
o
9-14
Seroresponses rate, GMT
M12
12-15
GMT
M7
o
15-25
Seroresponses rate, GMT
M7
●
18-45
Seroresponses rate, GMT
M60
x
qHPV
2-dose
3-dose
2-dose
xx
xx
xx
x
Similar symbols indicate where comparative analyses were performed
The following immunological assays were used for immunogenicity evaluation:
•
Pseudovirion-Based Neutralization Assay (PBNA) was used to assess non-inferiority versus
qHPV 1 month after the last dose (Month 7) as the primary immunogenicity endpoint in study
HPV-010. The assay was also used for assessment of secondary immunogenicity objectives
(e.g. long-term antibody persistence) in the same study and in study HPV-071.
•
Enzyme-linked Immunosorbent Assay (ELISA) was used for the assessment of non-inferiority
and superiority versus qHPV at Month 7 in study HPV-071 (primary immunogenicity endpoint)
and for the immunogenicity assessments in studies HPV-011 and HPV-040. The ELISA assay
was also used for secondary immunogenicity endpoints in study HPV-010 (non-inferiority
versus qHPV at different time points).
2.4.1. Main studies
Studies documenting immunogenicity and safety of Cervarix in females
•
HPV-010 demonstrates superiority of immune response to Cervarix over qHPV in healthy
females aged 18-45 years in a 3-dose schedule. Final study results up to Month 60 are
submitted herein. Interim study results were previously submitted (Variation II-36, published).
•
HPV-071 demonstrates superiority of immune response to Cervarix in healthy females aged 914 years in a 2-dose schedule over qHPV administered in a 2-dose and in a 3-dose schedule
(ELISA). Interim study results up to Month 12 are submitted herein. PBNA was performed in a
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subset and results are in line with ELISA. This study was ongoing at the time of the initial
submission for this application (see further below).
Studies documenting immunogenicity and safety of Cervarix in males
•
HPV-011 was a Phase I/II study that demonstrated immunogenicity and acceptable safety in
healthy males aged 10-18 years in a 3-dose schedule. Immune responses elicited by Cervarix
in males (10-18 years of age) are non-inferior (in terms of seroconversion rates and GMTs) to
immune responses elicited by Cervarix in females 15-25 years of age (the age range in which
vaccine efficacy was demonstrated) enrolled in study HPV-012. Final study results at Month 12
were previously submitted (FUM 28).
•
HPV-040 is a Phase III/IV study that demonstrated immunogenicity and acceptable safety in
healthy males aged 12-15 years in a 3-dose schedule. This study was ongoing when this
application started. Interim results at Month 7 were previously submitted (FUM 34).
Study HPV-009
In addition, the MAH referred to post-hoc data originated from the clinical efficacy study HPV-009,
conducted by the National Cancer Institute (NCI, US) in collaboration with GSK i.e. the Costa Rica
Vaccine Trial (CVT), to support the current application with vaccine efficacy data against clinical
endpoints such as anal and cervical infection.
Inclusion criteria for all studies
Healthy subjects (of ages 9 years - 45 years) were enrolled in all studies, for whom the investigator
believed that they and/or their parents/ Legally acceptable representative(s) (LARs) could and would
comply with the requirements of the protocol. Written informed consent was obtained from the subject
prior to enrolment and any study procedure. For subjects below the legal age of consent, a written
informed consent was obtained from the subject’s parent/LAR, and a written informed assent was
obtained from the subject. For study HPV-040, for subjects above legal age of consent, written
informed consent was obtained from the subject and an information letter was provided to their
parent/LAR(s).
Exclusion criteria for all studies
In general, the objective of the exclusion criteria was to prevent the administration of the study
vaccine to individuals with medical conditions that could potentially interfere with the evaluation of the
immune response, and to individuals at risk of possible adverse reaction to a vaccine. Subjects were to
be free of obvious health problems as established by medical history and clinical examination. In case
of female subjects, they had to be of non-childbearing potential or, if of childbearing potential, had a
negative pregnancy test on the day of vaccination, had to be abstinent or had to be using adequate
contraceptive precautions for 30 days prior to vaccination and had to agree to continue such
precautions for two months after completion of the vaccination series. No previous vaccination against
HPV or hepatitis B (studies with Engerix-B as control) was allowed.
2.4.1.1. HPV-010
This study was a phase IIIb, observer-blind, randomized (1:1), multicentre study with two parallel
groups to compare the immunogenicity of Cervarix versus qHPV, when administered intramuscularly
according to a 3-dose schedule in healthy adult females 18-45 years of age. This study was a
multicentre study conducted in 40 centres located in the USA.
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The clinical study report for study HPV-010 (from Month 7 till Month 48) was previously submitted and
assessed in the frame of EMEA/H/C/00721/II/036 (CHMP assessment report published). For this
reason, only a brief summary of the study design and statistical methods are given below. The
submission of the final report at Month 60 is discussed herein.
Methods
Recruitment
Healthy females 18-45 years of age were arranged in two parallel groups:
•
One group received the GSK HPV vaccine (N=553)
•
One group received the qHPV vaccine (N=553)
Enrolment into each treatment group was age-stratified with a slightly greater number of subjects in
the 18-26 year-old cohort (417 subjects) than in the 27-35 year-old cohort (356 subjects) or the 3645 year-old cohort (333 subjects).
For inclusion and exclusion criteria see section 2.4.1.
Treatment and blinding
Three doses of vaccine were administered according to the recommended schedule for Cervarix (0, 1,
6-months) and qHPV (0, 2, 6-months). To maintain blinding, all subjects received injections at Months
0, 1, 2 and 6. Placebo [Al(OH)3] was administered at either Month 2 (Cervarix recipients) or Month 1
(qHPV recipients). The subjects, investigator, study personnel and MAH staff remained blinded until
completion of study follow-up. The method of data collection occurred through Remote Data Entry
(RDE). Five visits were scheduled per subject on Day 0, at Months 1, 2, 6 and 7 in the active phase.
Additionally, there were 6 follow-up study visits scheduled at Months 12, 18, 24, 36, 48 and 60. A
cervical sample was collected from all subjects for HPV deoxyribonucleic acid (DNA) testing on Day 0.
Blood samples of 20 mL were collected from all subjects on Day 0, at Months 6, 7, 12, 18, 24, 36, 48
and 60 for evaluation of antibody response. An additional 50 mL blood sample on Day 0, at Months 7,
12, 18, 24, 36 and 48 was collected for evaluation of CMI response in a subset of subjects from preselected sites. Cervico-vaginal Secretion Sample (CVS) were collected for HPV-16/18 antibody testing
on Day 0, at Months 7, 12, 18, 24, 36 and 48 in a subset of subjects from preselected sites.
Between-group comparisons
•
Primary between-group comparisons to assess superiority were performed in the total
vaccinated cohort (TVC). At Month 7, the inferential analyses were statistically powered.
•
At subsequent time points, including Month 60, inferential statistics were exploratory.
Non-inferiority and superiority criteria
For each serology assay (PBNA and/or ELISA), for each treatment group (Cervarix and qHPV), for each
age group (18-26, 27-35 and 36-45 years of age), at each time point that a blood sample result was
available: i) Seropositivity rates for HPV-16, HPV-18, HPV-31 and HPV-45 antibodies (with exact 95%
confidence interval [CI]) were calculated; ii) GMT with 95% CI and range of antibody titres were
tabulated for antibodies against HPV-16, HPV-18, HPV-31 and HPV-45.
•
If the lower limits of the two-sided 97.6% confidence interval (CI) for the GMT ratios (Cervarix
divided by qHPV) for anti-HPV-16 and anti-HPV-18 antibodies were above 0.5, non-inferiority
of Cervarix to qHPV was to be concluded.
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•
If the lower limit of the two-sided 97.6% CI for the ratio of GMTs of a given antigen was above
1, the p-value associated with a test of superiority was also to be calculated for that antigen.
Study cohorts
•
The Month 7 ATP cohort for immunogenicity consisted of 370 subjects in the Cervarix group
and 364 subjects in the qHPV group.
•
The Month 7 TVC consisted of 553 subjects in the two groups.
•
The Month 60 ATP cohort for immunogenicity consisted of 159 subjects in the Cervarix group
and 156 subjects in the qHPV group and the TVC consisted of 213 subjects in the Cervarix
group and 208 subjects in the qHPV group.
Demographic characteristics
•
The demographic profile of subjects in the Month 60 ATP cohort for immunogenicity was
comparable between the two vaccine groups with respect to age (mean age in years:
31.6±7.68 in Cervarix group vs. 31.5±8.06 in qHPV group) and ethnicity/racial distribution
(predominantly Caucasian and European: 88.7% in Cervarix vs. 87.8% in qHPV group). A
similar demographic profile was seen in the TVC.
Study endpoints for immunogenicity
•
The primary endpoint was HPV-16/18 geometric mean antibody titre (GMT) assessment by
PBNA at M7 in healthy adult females 18-26 years of age.
•
•
The secondary endpoints included the immunogenicity assessment using PBNA of
−
HPV-16/18 antibody titres at M7 in healthy adult females 27-35 and 36-45 years of age.
−
HPV-16/18 seroconversion status at M7 in healthy adult females 18-26 years of age.
−
HPV-16/18 seroconversion status at M7 in healthy adult females 27-35 and 36-45 years.
−
HPV-16/18 antibody titres and seroconversion status at M6, 12, 18, 24, 36, 48 and 60.
The secondary endpoints included the immunogenicity assessment using ELISA of
−
HPV-16/18 antibody titres and seroconversion status at M 6, 7, 12, 18, 24, 36, 48 and 60.
Other secondary endpoints were also assessed in this study, but they are not relevant for the purpose
of this application (for details see assessment report of variation II-36).
Results for study HPV-010
Study results for HPV-010 for the time points 7 Months, 24 Months and 60 Months have been
published (Einstein, 2009; Einstein, 2011; Einstein, 2014). The most relevant results for this
application are reported as follows.
Immunogenicity analysis at Month 7
The primary endpoint was met. All initially seronegative and DNA negative subjects in the Cervarix
group seroconverted as measured by neutralisation assay at Month 7 for both HPV-16 and HPV-18. In
the qHPV group all but two subjects (in the 27-35 age group for HPV-18) who were initially
seronegative and DNA negative for HPV-18 seroconverted at Month 7. The primary objective of the
study, i.e. the comparison of the GMTs (PBNA) of HPV-16 and -18 serum antibodies at Month 7 after
first vaccination with Cervarix or qHPV in women aged 18–26 years old, showed non-inferiority and
superiority of the antibody response elicited by Cervarix vaccination over qHPV. The HPV-16 GMTs for
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the Cervarix group were 3.66-fold (2.56; 5.23) higher than for the qHPV group. Similarly, the HPV-18
GMT was 7.30-fold higher (5.14; 10.37) for the Cervarix group than the qHPV group. As the lower
limits of the confidence intervals were greater than 0.5, non-inferiority was demonstrated. Noninferiority was also demonstrated for the 27-35 age group as well as the 36-45 age group for both HPV
types. Compared with qHPV, anti-HPV-16 and -18 GMTs with Cervarix were respectively 4.8-fold (3.3;
7.1) and 9.1- fold (6.0; 13.8) higher in women aged 27–35 years and 2.3-fold (1.5; 3.4) and 6.8-fold
(4.6; 10.2) higher in women aged 36–45 years.
The primary superiority assessment was performed in the TVC (regardless of serostatus and DNA
status at baseline) and demonstrated superiority of the antibody titres in the Cervarix group versus
qHPV for all age groups and for both HPV-16 and HPV-18 (p value< 0.0001). Superiority was
concluded if the p-value was ≤ 0.024.
Persistence of immune response as measured by PBNA after vaccination (Month 60 analysis, secondary
endpoint)
1. Anti-HPV-16 immune response in seronegative and DNA negative subjects at baseline (Month
60 ATP cohort for immunogenicity)
All initially seronegative and DNA negative subjects in the Cervarix group remain seropositive by PBNA
for HPV-16 antibodies at Month 60, in all the age strata. In the qHPV group, depending on the age
stratum, 95.7% to 97.5% of subjects remained seropositive for HPV-16 antibodies at Month 60.
HPV-16 antibody levels were higher in the Cervarix group when compared with the qHPV group for all
age strata (7.77-fold (4.31; 14.02) in the 18-26 age group, 5.56-fold (3.03; 10.19) in the 27-35 age
group and 2.23-fold (1.27; 4.29) in the 36-45 age group).
The kinetics of HPV-16 neutralising antibody levels (measured by PBNA) were analysed in the Month
60 kinetic cohort of subjects that were seronegative and DNA negative at baseline for the HPV type
analysed and that had data available for all time points. For both vaccines, the GMTs for HPV-16
antibodies (PBNA) remain above the level obtained through natural HPV infection (ED50: 180.1). The
natural infection level has been defined as the mean antibody titre to a specific HPV-type in subjects
seropositive and DNA negative for the same type prior to vaccination with Cervarix (i.e. subjects who
have cleared a previous HPV infection) (Einstein, 2009). Figure 1 below shows the kinetics up to Month
60 in the 18-26 years stratum. The other 2 age strata showed similar trends.
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Figure 1. GMTs with 95% CI for HPV-16 PBNA antibodies in female subjects seronegative (by PBNA)
and DNA negative (by PCR) at baseline (kinetic cohort) - 18-26 years stratum
2. Anti-HPV-18 immune response in seronegative and DNA negative subjects at baseline (Month
60 ATP cohort for immunogenicity)
In the Cervarix group, 98.1% to 100% of initially seronegative and DNA negative subjects were still
seropositive for HPV-18 antibodies at Month 60 (one subject in the 27-35 age group was tested
seronegative at Month 60). In the qHPV group, 61.1% to 76.9% of subjects were still seropositive for
HPV-18 antibodies at Month 60.
For seronegative and DNA negative subjects at baseline, HPV-18 antibody levels were higher in the
Cervarix group when compared to the qHPV group for all age strata (12.07-fold (6.60; 22.08) in the
18-26 age group, 13.00-fold (7.59; 22.25) in the 27-35 age group and 7.76-fold (4.53; 13.29) in the
36-45 age group).
The kinetics of HPV-18 neutralising antibody levels (measured by PBNA) were analysed in the Month
60 kinetic cohort of subjects that were seronegative and DNA negative at baseline for the HPV type
analysed and that had data available for all time points. The kinetics up to Month 60 are shown in
Figure 2 for the 18-26 years stratum. In the other 2 age strata, whereas the GMTs within the Cervarix
group remained sustainably above the level obtained through natural infection (ED50: 137.3), the
GMTs in the qHPV group dropped below that level from Month 18 in the 27 to 35 years stratum, and
from Month 36 in the two other age strata (not shown).
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Figure 2. GMTs with 95% CI for HPV-18 PBNA antibodies in female subjects seronegative (by PBNA)
and DNA negative (by PCR) at baseline (kinetic cohort) - 18-26 years stratum
3. Exploratory inferential statistics at Month 60
Exploratory inferential analyses were performed with a type I error of 5%. Statistically significant
differences (p-value [p] ≤ 0.05) should be interpreted with caution considering that there was no
adjustment for multiplicity of comparisons and that the clinical relevance of the difference is unknown.
The analysis determined non-inferior GMTs in the Cervarix group as compared to the qHPV group in
subjects seronegative and DNA negative at baseline (Month 60 ATP cohort for immunogenicity) (not
shown).
The subsequent superiority test showed GMTs of HPV-16 and HPV-18 (PBNA) antibodies at Month 60 in
the Cervarix group to be higher than those in the qHPV group in TVC regardless of baseline serostatus,
across the three age strata (table 2).
Table 2. Superiority assessment in terms of antibody titres between Cervarix and qHPV for HPV16
and HPV18 PBNA antibodies at Month 60 (Total Vaccinated cohort)
4. Immune response measured by ELISA
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Overall, for HPV-16 and HPV-18, analyses by ELISA corroborated the results observed by PBNA.
As an overall conclusion for study HPV-010, in females 18-45 years of aged who received Cervarix
according to a 3-dose schedule, final study results up to Month 60 show that GMTs for antibodies
against both HPV-16 and HPV-18 reached a peak response at Month 7, showed a decline up to Month
12 in all three groups, and then remained relatively stable over time and always higher than qHPV.
2.4.1.2. Study HPV-071
HPV-071 is a Phase IIIb observer-blind, randomized, multi-centre trial (Sweden, Hong Kong, France
and Singapore), which was ongoing at the time of the submission of this application (completed in
December 2015). Interim results up to Month 12 were submitted for this application. The study design
is shown below:
Methods – analysis of data submitted
Recruitment
•
Females aged 9-14 years
For inclusion and exclusion criteria see section 2.4.1.
Treatment groups
•
3 parallel groups
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−
•
Cervarix according to a 2-dose schedule (0, 6 months)
−
qHPV according to a 2-dose schedule (0, 6 months)
−
qHPV according to a 3-dose schedule (0, 2, 6 months)
The two groups vaccinated according to the 2-dose schedule received one dose of placebo at
Month 2 to maintain study blind (observer-blind).
Study objectives
•
The primary objective of the trial was to evaluate sequentially if the immunogenicity (as
determined by ELISA) of Cervarix was non-inferior/superior to that of qHPV one month after
the last dose (Month 7) according to a 2-dose schedule at 0, 6 months in 9-14 years old
females.
•
First secondary objective: if non-inferiority at Month 7 was shown, non-inferiority/superiority
analysis by comparison of the immune response to both vaccine antigens between the Cervarix
2-dose group and the qHPV 2-dose group at Months 12, 18, 24 and 36 will be performed.
•
Additional secondary objective: if the primary non-inferiority objective was reached, a
secondary objective was to evaluate sequentially and at the different time points if the
immunogenicity of Cervarix administered according to a 2-dose schedule at 0, 6 months was
non-inferior/superior to that of qHPV administered according to the standard 3-dose schedule
at 0, 2, 6 months. The immune responses to HPV types 16 and 18 by PBNA in a subset of
subjects at the different time points up to Month 36 were additional secondary objectives as
well. See also table below:
Table 3. Immunogenicity objectives for study HPV-071
Numbers of subjects in the different cohorts are presented below:
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Table 4. Number of subjects in HPV-071
Demographic characteristics
•
In the ATP cohort, the age at vaccination was comparable between the different groups (11.5 ±
1.62 years in Cervarix group, 11.5 ± 1.55 years in qHPV 2-dose group and 11.6 ± 1.63 years in
qHPV 3-dose group).
•
The three groups had a comparable ethnical/racial distribution, with an approximate 50% of
the subjects in each group of East Asian heritage and an approximate 25% of Caucasian
heritage. Demographic characteristics in the TVC were similar.
Study endpoints
•
Primary endpoints are the assessment of anti-HPV-16/18 seroconversion rates and antibody
titres by ELISA, one month after the last dose of study vaccine (Month 7). For each HPV
antigen (HPV-16 and HPV-18), the immune response in terms of seroconversion rates and
GMTs at Month 7 was compared sequentially between the Cervarix group and the qHPV group
by non-inferiority and superiority analyses.
•
Secondary endpoints for immunogenicity:
−
If the primary non-inferiority objective is reached, the next objective is to evaluate
sequentially if the immunogenicity (as determined by ELISA) of Cervarix administered
according to a 2-dose schedule at 0, 6 months is non-inferior/superior to that of qHPV
administered according to a 2-dose schedule at 0, 6 months at Months 12, 18, 24 and
36.
−
If the primary non-inferiority objective is reached, the next objective is to evaluate
sequentially if the immunogenicity (as determined by ELISA) of Cervarix administered
according to a 2-dose schedule at 0, 6 months is non-inferior/superior to that of qHPV
administered according to the standard 3-dose schedule at 0, 2, 6 months at Months 7,
12, 18, 24 and 36.
−
To assess the immune responses to HPV types 16 and 18 by ELISA at Day 0 and
Months 7, 12, 18, 24 and 36 in all subjects.
−
To assess the immune responses to HPV types 16 and 18 by PBNA in a subset of
−
To assess cell-mediated immunity (CMI), i.e., T-cell-mediated and memory B-cell
subjects at Day 0 and Months 7, 12, 18, 24 and 36.
immune responses specific to HPV-16 and HPV-18 in a sub-cohort of subjects at Day 0,
Months 7, 12, 24 and 36.
•
Secondary endpoints for safety:
−
To assess the reactogenicity of the administered vaccines in all groups after each dose.
−
To assess the safety of the administered vaccines in all groups.
−
To evaluate compliance with completion of vaccination in all groups.
Comparison between groups
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•
Primary between-group comparisons to assess the non-inferiority at Month 7 were performed
in the ATP cohort for immunogenicity on subjects seronegative by ELISA at Day 0 for the
antigen under analysis. Subjects seropositive for only one antigen were eliminated for the
analysis of that antigen but were still evaluable for the analysis of the other antigen. In
addition, non-inferiority assessment was also performed in the TVC on all subjects (regardless
of serostatus at Day 0).
•
Between-group comparisons to assess superiority were performed in the TVC on all subjects
(regardless of serostatus at Day 0). In addition, superiority assessment was also performed in
the ATP cohort for immunogenicity on subjects seronegative at Day 0 for the antigen under
analysis.
Criteria for non-inferiority
•
Non-inferiority with respect to seroconversion rates was shown if, one month after the last
dose, for both anti-HPV-16 and anti-HPV-18 antibodies the upper limit of the 95% CI for the
difference (qHPV minus Cervarix) was below 5%.
•
Non-inferiority with respect to GMT for both anti-HPV-16 and anti-HPV-18 antibodies was
shown if, one month after the last dose, the upper limit of the 95% CI for the GMT ratio (qHPV
divided by Cervarix) was below 2.
Criteria for superiority
•
If non-inferiority was reached, and if the lower limit of the two-sided 95% CI for the ratio of
GMTs Cervarix divided by qHPV of a given antigen was above 1 in the ATP cohort for
immunogenicity, the following criteria for superiority were to be assessed sequentially in the
TVC:
−
First, superiority for HPV-18 was assessed. Superiority was shown if the lower limit of
the 95% CI for the ratio of GMTs for anti-HPV-18 antibodies (Cervarix divided by
qHPV) was above 1 with the associated p-value.
−
Second, if superiority for HPV-18 is shown, superiority for HPV-16 was assessed.
Superiority was shown if the lower limit of the 95% CI for the ratio of GMTs for antiHPV-16 antibodies (Cervarix divided by qHPV) was above 1 with the associated pvalue.
Results and discussion for Study HPV-071
HPV-16/18 serostatus at baseline
The majority of subjects was initially seronegative for both HPV-16 and HPV-18, i.e. 96% in all groups
(Table 5).
Table 5. Seropositivity status at Baseline (ATP cohort for immunogenicity)
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Non-inferiority analysis on primary objective (Cervarix 2-dose vs qHPV 2-dose, Month 7)
Non-inferiority assessment of seroconversion rates is presented in Table 6 at one month after the last
dose (Month 7) in initially seronegative subjects (ATP cohort for immunogenicity). Non-inferiority
assessment of anti-HPV-16 and anti-HPV-18 antibody GMTs as measured by ELISA is presented in
Table 7.
Table 6. Non-Inferiority assessment of seroconversion rates one month after the last dose (Month 7)
in initially seronegative subjects (ATP cohort for immunogenicity)
Antibody
Cervarix
2-dose
N
%
Difference in seroconversion rate
(qHPV minus Cervarix)
qHPV
2-dose
N
%
Difference
qHPV minus Cervarix
qHPV minus Cervarix
%
0.00
0.00
95 % CI
LL
UL
-1.16
1.15
-1.15
1.14
HPV-16
330
100
327
100
HPV-18
334
100
331
100
N = number of subjects with available results
% = percentage of subjects with anti-HPV-16 antibody concentration ≥ 19 EU/ml; percentage of subjects with anti-HPV-18
antibody concentration ≥ 18 EU/ml
95% CI = 95% Standardized asymptotic confidence interval; LL = lower limit, UL = upper limit
Non-inferiority criterion: the upper limit of the 95% CI for the difference in seroconversion rates (qHPV minus Cervarix) is
below 5%
Table 7. Non-Inferiority assessment of anti-HPV-16 and anti-HPV-18 immune response one month
after the last dose (Month 7) in initially seronegative subjects (ATP cohort for immunogenicity)
Antibody
Cervarix
2-dose
qHPV
2-dose
GMT ratio
(qHPV / Cervarix )
95% CI
Value
LL
UL
0.54
0.69
0.20
0.26
N
GMT
N
GMT
HPV-16
330
8244.1
327
5056.0
0.61
HPV-18
334
5277.4
331
1207.2
0.23
GMT = geometric mean antibody titre
N = Number of subjects with pre-vaccination results available
95% CI = 95% confidence interval for the GMT ratio (Anova model - pooled variance); LL = lower limit, UL = upper limit
Non-inferiority criterion: the upper limit of the 95% CI for the GMT ratio (qHPV 2-dose schedule divided by Cervarix 2-dose
schedule) is below 2
Superiority analysis on primary objective (Cervarix 2-dose vs qHPV 2-dose, Month 7)
Because non-inferiority was reached, and the lower limit of the two-sided 95% CI for the ratio of GMTs
Cervarix divided by qHPV of a given antigen was above 1 in the ATP cohort for immunogenicity, a
superiority analysis was performed (table 8).
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Table 8. Superiority assessment of immune response one month after the last dose (Month 7, TVC)
Cervarix
2-dose
Antibody
GMT ratio
(Cervarix / qHPV)
95% CI
LL
UL
1.49
1.91
3.97
5.13
qHPV
2-dose
N
GMT
N
GMT
Value
HPV-16
357
8256.4
353
4886.1
1.69
HPV-18
357
5267.8
353
1166.3
4.52
GMT = geometric mean antibody titre
N = Number of subjects with post-vaccination results available
95% CI = 95% confidence interval for the GMT ratio (Anova model - pooled variance); LL = lower limit, UL = upper limit pvalue= 0.0001
Superiority criterion: the lower limit of the 95% CI for the ratio of GMTs for anti-HPV-16 and anti HPV-18 antibodies (Cervarix
2-dose schedule divided by qHPV 2-dose schedule) is above 1
Table 8 results show that the primary objective of the study was met.
In summary, after Cervarix vaccination as compared to qHPV vaccination, both administered according
to a 2-dose schedule in females aged 9-14 years of age, study HPV-071 demonstrated at Month 7:
•
Non-inferiority in terms of seroconversion rates
•
Superiority in terms of GMT ratio in the Total Vaccinated Cohort.
Non-inferiority analysis on secondary objective (Cervarix 2-dose vs qHPV 3-dose, Month 7)
Secondary objectives included assessment of anti-HPV-16/18 seroconversion rates and antibody titres
by ELISA at Day 0 and later time points.
The secondary objective to evaluate sequentially if the immunogenicity (as determined by ELISA) of
Cervarix administered according to a 2-dose schedule at 0, 6 months was non-inferior/superior to that
of qHPV vaccine administered according to the standard 3-dose schedule (0, 2, 6 months) at Month 7,
was met for this study (ATP cohort).
Table 9. Non-Inferiority assessment of seroconversion rates one month after the last dose (Month 7)
in initially seronegative subjects (ATP cohort for immunogenicity)
Antibody
Cervarix
2-dose
N
%
Difference in seroconversion rate
(qHPV minus Cervarix)
qHPV
3-dose
N
%
Difference
qHPV minus Cervarix
qHPV minus Cervarix
%
0.00
0.00
95 % CI
LL
UL
-1.18
1.15
-1.14
1.14
HPV-16
330
100
322
100
HPV-18
334
100
333
100
N = number of subjects with available results
% = percentage of subjects with anti-HPV-16 antibody concentration ≥ 19 EU/ml; percentage of subjects with anti-HPV-18
antibody concentration ≥ 18 EU/ml
95% CI = 95% Standardized asymptotic confidence interval; LL = lower limit, UL = upper limit
Non-inferiority criterion: the upper limit of the 95% CI for the difference in seroconversion rates (qHPV minus Cervarix) is
below 5%
Table 10. Non-Inferiority assessment of anti-HPV-16 and anti-HPV-18 immune response one month
after the last dose (Month 7) in initially seronegative subjects (ATP cohort for immunogenicity)
Antibody
Cervarix
2-dose
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qHPV
3-dose
GMT ratio
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95% CI
GMT
N
GMT
Value
LL
UL
HPV-16
330
8244.1
322
4807.4
0.58
0.52
0.65
HPV-18
334
5277.4
333
1653.5
0.31
0.27
0.36
GMT = geometric mean antibody titre
N = Number of subjects with pre-vaccination results available
95% CI = 95% confidence interval for the GMT ratio (Anova model - pooled variance); LL = lower limit, UL = upper limit
Non-inferiority criterion: the upper limit of the 95% CI for the GMT ratio (qHPV 3-dose schedule divided by Cervarix 2-dose
schedule) is below 2
N
Superiority analysis on secondary objective (Cervarix 2-dose vs qHPV 3-dose, Month 7, TVC)
In the TVC cohort, regardless of the HPV-16/18 serostatus at baseline, the GMT ratio (Cervarix 2-dose
schedule divided by qHPV 3-dose schedule) for HPV-18 was 3.22 (2.82; 3.68), and for HPV-16 it was
1.72 (1.54; 1.93). As the statistical test was met for both anti-HPV 16 and anti-HPV18 antibodies at
month 7, superiority was demonstrated (Table 11) (p-value=0.0001 for both antigens).
Table 11. Superiority assessment of anti HPV-16 and anti-HPV-18 immune response for (Cervarix 2dose vs qHPV 3-dose) one month after the last dose (Month 7) (Total Vaccinated cohort)
Non-inferiority analysis on secondary objective (Cervarix 2-dose vs qHPV 2-dose or 3-dose, Month 12)
As the primary non-inferiority/superiority objectives at Month 7 were reached, the protocol required
that they be repeated at Month 12 as secondary objectives.
Of subjects who seroconverted one month after finalisation of the vaccination schedule (Month 7
analysis), all subjects in the qHPV 2-dose and qHPV 3-dose groups and all but one in the Cervarix 2dose group were still seropositive for anti-HPV-16 antibodies when measured by ELISA. For HPV-18
antibodies, all subjects in the qHPV 3-dose group and all but one initially seronegative subject in the
qHPV 2- dose and Cervarix 2-dose groups remained seropositive, when measured by ELISA.
GMTs for antibodies against both HPV-16 and HPV-18, which had reached a peak response at Month 7,
showed a decline at Month 12 in all three groups, but remained higher in Cervarix group as compared
to both qHPV groups. This is in line with the observations for study HPV-010.
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Figure 3. Anti-HPV-16 and anti HPV-18 antibody titres (ELISA) in initially seronegative subjects
(Month 12 ATP cohort for immunogenicity)
Sequential non-inferiority and superiority assessments at Month 12
At Month 12, non-inferiority of the immune response to 2 doses of Cervarix compared to 2 doses of
qHPV at Month 12 in terms of seroconversion rates was demonstrated as the statistical criteria
described before were met. The upper limit of the 95% CI for the GMT ratio (qHPV 2-dose group
divided by Cervarix 2-dose group) for anti-HPV-16 and anti-HPV-18 antibodies was 0.67 and 0.23,
respectively (i.e., below 2). Therefore, non-inferiority of GMTs after Cervarix vaccination as compared
to qHPV vaccination, both in a 2-dose schedule, was demonstrated at Month 12 (ATP cohort).
Superiority of the immune response in terms of GMTs was also met at Month 12 in the TVC cohort,
i.e., the lower limit of the 95% CI for the GMT ratio (Cervarix 2-dose divided by qHPV 2- dose) for
anti-HPV-18 and anti-HPV-16 antibodies was above 1 (4.27 and 1.53, respectively, Month 12 TVC (pvalue=0.0001 for both antigens).
For the comparison of Cervarix 2-dose group versus qHPV 3-dose group, non-inferiority of the immune
response to 2 doses of Cervarix compared to 3 doses of qHPV at Month 12 in terms of seroconversion
rates was demonstrated as the statistical criteria described before were met (ATP cohort). Noninferiority at Month 12 in the ATP cohort for immunogenicity was also demonstrated when comparing
the GMTs after Cervarix administration in a 2-dose schedule versus qHPV in a 3-dose schedule. The
upper limit of the 95% CI for the ratio (qHPV 3-dose schedule divided by Cervarix 2-dose schedule) for
anti-HPV-16 and anti-HPV-18 antibodies was 0.82 and 0.43, respectively (i.e., below 2).
Superiority of the immune response in terms of GMTs was demonstrated for the Cervarix 2-dose
schedule over the qHPV 3-dose schedule as well, according to the statistical criteria described before
(TVC cohort). The lower limit of the 95% CI for the ratio (Cervarix 2-dose schedule divided by qHPV 3dose schedule) for anti-HPV-16 and anti-HPV-18 antibodies was 2.37 and 1.24, respectively (i.e. above
1) (p-value=0.0001 for both antigens).
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Table 12. Superiority assessment of anti HPV-16 and anti HPV-18 immune response for (Cervarix 2dose vs qHPV 3-dose) at Month 12 (Month 12 Total Vaccinated cohort)
These persistence data demonstrate that the observed non-inferiority and superiority of the immune
response to Cervarix administered in a 2-dose schedule as compared to qHPV vaccination and
irrespective of the vaccination schedule, in terms of seroconversion rates as well as GMTs for both
anti-HPV-16 and anti-HPV-18 antibodies at Month 7, is maintained at least up to Month 12.
Anti-HPV-16/18 neutralising antibodies measured by PBNA at Month 12
The data generated at Month 12 with PBNA, specifically measuring neutralising antibodies, complement
the data and conclusions drawn from the ELISA measurements.
Of all subjects that had seroconverted one month after the last vaccination (Month 7), all remained
seropositive for anti-HPV-16 neutralising antibodies when measured by PBNA. For HPV-18, all subjects
in the Cervarix 2-dose and qHPV 3-dose groups remained seropositive as well. In the qHPV 2-dose
group, the antibody titre at Month 12 was below the cut-off value for seropositivity for the assay (40
ED50) for two subjects out of 93.
GMTs for neutralising antibodies against both HPV-16 and HPV-18 reached a peak response at Month 7
then declined to Month 12 in all three groups, in line with the data from study HPV-010. No statistical
inferential analysis was performed to compare GMTs as measured with PBNA. These descriptive data
are however in line with those obtained using ELISA testing, and suggest higher neutralising antibody
titres in the Cervarix 2-dose group as compared to the two qHPV groups (2-dose and 3-dose).
2.4.1.3. Study HPV-011
This study was a phase I/II, observer-blind, randomised, controlled study to assess the
immunogenicity and safety of Cervarix administered intramuscularly according to a 0, 1, 6 month
schedule in healthy male subjects 10-18 years of age. The study was conducted in multiple centres in
Finland. A total of 270 subjects were enrolled.
The clinical study report from study HPV-011 (Month 7 and Month 12) was previously submitted and
assessed within the post-authorisation measure 028 (please refer to Rapporteur’s Assessment Report
for this procedure for details). For a brief summary of the study design and statistical methods see the
tabular overview of clinical studies (section 2.3).
Treatment and randomisation
For inclusion and exclusion criteria see section 2.4.1.
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Subjects were randomly allocated (2:1) to receive either Cervarix or GSK Biologicals’ Hepatitis B
vaccine, Engerix B, as control. Randomisation was age-stratified (10-12 years, 13-15 years and 16-18
years). All subjects were vaccinated according to a 0, 1, 6-month schedule. The duration of the study
(including safety follow-up) per subject was approximately 12 months, with the last study visit at
Month 7 and a telephone contact at Month 12.
Objectives
The primary objective of the study was to evaluate one month after the third dose (i.e. at Month 7),
the immune responses to Cervarix, as determined by anti-HPV-16/18 ELISA in healthy male subjects
aged 10-18 years old.
Secondary objectives included the evaluation of non-inferiority of the immune responses to Cervarix
(as determined by anti- HPV-16/18 ELISA) in healthy male subjects aged 10–18 years in this study as
compared to the responses measured in sera from a subset of 15-25 years old females from the HPV012 study (the age range in which vaccine efficacy was demonstrated), one month after administration
of the third vaccine dose (i.e. at Month 7). The evaluation of the immune response (ELISA) to Cervarix
one month after the second dose (i.e. at Month 2) was a secondary objective of the study.
Immunogenicity analysis
The primary analysis of the immunogenicity (seropositivity and GMTs) was performed in the ATP
cohort for immunogenicity. Non-inferiority evaluation for GMTs versus subjects from study HPV-012
was also performed based on the ATP cohort for immunogenicity.
For the Cervarix group, the ATP cohort for immunogenicity consisted of 173 subjects. The noninferiority assessment for GMTs in the ATP cohort was based on a comparison with data from 359 and
364 female subjects from study HPV-012 for HPV-16 and HPV- 18 respectively.
Baseline data
The mean age in the Cervarix group of HPV-011 was 14.4
± 2.14 years and the population was
predominantly of Caucasian heritage (97.8%). In comparison, the demographic profile of the
comparative HPV-012 female population had a mean age of 20.2
± 2.9 years with 96.3%
white/Caucasian heritage.
Statistical methods and analyses
The primary endpoint of the study was the assessment of HPV-16 and HPV-18 seroconversion rates
and geometric mean titres (GMTs) at Month 7. The secondary endpoint was assessment of HPV-16 and
HPV-18 seroconversion rates and GMTs at Month 2.
Comparison between groups
The secondary study objectives included non-inferiority analysis of the immune responses to Cervarix
in healthy male subjects aged 10–18 years in this study, compared to the responses measured in sera
from a subset of 15-25 years old females from the HPV-012 study, one month after administration of
the third vaccine dose (i.e. at Month 7).
The following criteria for non-inferiority applied:
•
Seroconversion: one month after the third dose, the upper limits of the 95% CI on the
difference of seroconversion rates for HPV-16 and HPV-18 between the 15-25 years old female
subjects of the Cervarix group in study HPV-012 and the 10-18 years old males in the Cervarix
group of study HPV-011 were below 10%.
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•
GMT ratios: one month after the third dose, the upper limit of the 95% CI on the GMT ratios
for HPV-16 and HPV-18 between the 15-25 years old females group of study HPV-012 and the
10-18 years old males in the Cervarix group of study HPV-011 was below 2.
Results for study HPV-011
Descriptive immunogenicity analysis in males as primary objective
Analysis of immunogenicity was performed on the ATP cohort for immunogenicity (primary analysis)
and the TVC (secondary analysis).
After vaccination, all subjects (seropositive and seronegative at baseline) in the Cervarix group were
seropositive at one month post dose 2 (Month 2) and remained seropositive up to one month post
dose 3 (Month 7) for both HPV-16 and HPV-18.
High GMTs were observed in the Cervarix group at Month 2 (5,221.1 (4,660.8; 5,848.7) for HPV-16
and 3,663.8 (3,217.9; 4,171.6) and HPV-18), with approximately a four-fold increase for HPV-16 and
a two-fold increase for HPV-18 between Month 2 and Month 7 (22,639 (19,825.5; 25,853.4) for HPV16 and 8,416.1 (7,215.0; 9,817.1) HPV-18 at Month 7).
By age category (10-14 years and 15-18 years), higher GMTs were observed in the younger age group
than in the older age group at Month 7. The Month 7 results of study HPV-011 have been published
(Petäjä, 2009).
Non-inferiority assessment between males in study HPV-011 and females in study HPV-012
As secondary objective, the immunogenicity results in the 10 to 18 years old males in study HPV-011
were compared to the results in the 15 to 25 years old females from study HPV-012 (inter-study
inferential analysis). Of note, the HPV-012 study results have been presented in the initial Marketing
Authorisation Application (MAA) and have been published (Pedersen, 2007; Petäjä, 2011). HPV-012
was a pivotal study for the Cervarix MAA because it showed higher immunogenicity in the 10-14 yearolds population vs. the 15-25 year-olds population in which clinical efficacy was demonstrated (clinical
efficacy trials HPV-001 and 008 of the MAA).
The comparison concerned demonstration of non-inferiority in males 10-18 years versus females 15-25
years for HPV-16/18 seroconversion rates and HPV-16/18 antibody GMTs, one month after
administration of the third vaccine dose (i.e. at Month 7).
As shown in tables 13 and 14, the secondary immunogenicity objective of the study was met, as noninferiority of the immune response in males versus females was demonstrated both for seroconversion
rates and GMTs for HPV-16/18 antibodies. Concerning the seroconversion rate, one month after the
third dose, the upper limits of the 95% CI on the difference in seroconversion rates between the
female and the male subjects were below the pre-defined non-inferiority criterion of 10% for both HPV
types. With regards to the GMTs, the upper limit of the 95% CI on the GMT ratios between females
and males were below the pre-defined non-inferiority limit of 2 for both HPV types. Therefore, this
inter-study inferential analysis between males and females demonstrates comparability of immune
responses to Cervarix between genders, but more importantly non-inferiority of the immune response
of 3 doses of Cervarix in males 10-18 years as compared to 3 doses of Cervarix in females 15-25 years
(the population in which efficacy against cervical lesions and cancer was demonstrated).
A sub-analysis of antibody titres was performed for the age groups 10–14 and 15-18 years of age
separately. In both age groups 100% seroconversion was observed at Month 7 for both antigens and
overall higher GMTs were observed in the younger age group than in the older age group.
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Table 13. Non-inferiority assessment in terms of seroconversion rates between males (10-18 years
old) in study HPV-011 and females (15-25 years old) in study HPV-012, Post Dose III, Month 7 (ATP
cohort for immunogenicity)
Females
15-25 years
(HPV-012)
Antibody
Males
10-18 years
(HPV-011)
Difference in seroconversion rates
(females minus males)
95 % CI
Difference
%
LL
UL
Females - Males
0
-1.06
2.30
Females - Males
0
-1.04
2.50
N
%
N
%
HPV-16
359
100
163
100
HPV-18
364
100
150
100
N = number of subjects with available results
% = percentage of subjects with HPV-16 VLP IgG titres ≥ 8 EL.U/ml or HPV-18 VLP IgG titres ≥ 7 EL.U/ml
95% CI = 95% Standardised asymptotic confidence interval; LL = lower limit, UL = upper limit
Calculation performed on subjects seronegative prior to dose 1
Non-inferiority criterion: upper limit of the 95% CI around the difference in seroconversion rates below 10%
Table 14. Non-inferiority assessment in terms of GMT ratios between males (10-18 years old) in
study HPV-011 and females (15-25 years old) in study HPV-012, Post Dose III, Month 7 (ATP cohort
for immunogenicity)
Antibody
Females
15-25 years
(HPV-012)
N
GMT
359
7292.9
364
3318.8
Males
10-18 years
(HPV-011)
N
GMT
163
22639.7
150
8416.1
HPV-16
HPV-18
GMT = geometric mean antibody titres
N = Number of subjects with pre-vaccination results available
95% CI = 95% confidence interval for the GMT ratio (Anova model - pooled variance);
Calculation performed on subjects seronegative prior to dose 1
Non-inferiority criterion: upper limit of the 95% CI around the GMT ratio below 2
GMT ratio
(Females / Males )
95% CI
Value
LL
UL
0.32
0.27
0.38
0.39
0.33
0.47
2.4.1.4. Study HPV-040
This study is a phase III/IV, community-randomised, partially-blinded controlled study in 12–15 yearold male and female subjects, which was ongoing at the time of the submission of this application
(global end of trial date: 14 December 2015). HPV-040 is a multi-centre study conducted in Finland.
The objective of this study is to evaluate the effectiveness of vaccination with Cervarix in reducing the
prevalence of HPV-16/18 genital infection in females in communities where vaccination has been
introduced in girls only, compared with communities where vaccination has been introduced in girls
and boys. In the scope of the current submission however, study HPV-040 is presented to describe
immunogenicity and safety results of Cervarix in males.
Immunogenicity data (ELISA) of Cervarix in a subset of males and females, 7 months after first
vaccination, have been analysed whilst the study was ongoing and submitted in the current application
as an interim report (see further below). A brief summary of results at month 7 was already submitted
and assessed within the post-authorisation measure 034. The study was initiated on 04 October 2007
and the study completion date for last-subject/last-Month-12 contact for this interim analysis was 20
April 2011. The data lock point for immunogenicity analysis was 07 May 2012.
Methods
For a brief summary of the study design and statistical methods see the tabular overview of clinical
studies (section 2.3).
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The study includes two treatment groups: study participants who received Cervarix and study
participants who received GSK Biologicals’ hepatitis B vaccine Engerix B (HBV group).
The study design includes three arms (see also figure below):
•
Arm A includes communities (N = 11) where 90% of male and female adolescents were to be
vaccinated with Cervarix (vaccination strategy #1).
•
Arm B includes communities (N = 11) where 90% of the female adolescents were to be
vaccinated with Cervarix (vaccination strategy #2).
•
Arm C includes communities (N = 11) where the adolescents were not vaccinated against HPV16/18 (negative control). These male and female adolescents received Engerix B as negative
control.
Subjects in the Cervarix treatment groups received three doses of the vaccine according to a 0, 1, 6month schedule. Arm A of the study includes male subjects vaccinated with Cervarix. An interim
analysis was performed with the objectives to monitor the safety of Cervarix in males and females (all
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arms) and to assess the immunogenicity of the vaccine in a subset of males and females (Arm A
immunogenicity subset) at Month 7.
The primary analysis was based on the ATP cohort for analysis of immunogenicity (seropositivity rates
and GMTs), which included 556 males and 1,273 females vaccinated with Cervarix. A second analysis
based on the TVC for immunogenicity was performed to complement the ATP analysis. The TVC for
immunogenicity included 643 males and 1,472 females for the Cervarix group.
In the ATP cohort for immunogenicity, the mean age at the time of first vaccination in the Cervarix
group was 14.1
± 0.75 years, 69.5% of subjects were female and the population was predominantly of
Caucasian / European origin (98.5%).
Statistical analysis
Anti-HPV-16/18 antibody levels were assessed at Month 0 and Month 7 as a secondary endpoint at
interim analysis (study participants in the immunogenicity subset).
No statistically powered inferential analyses were performed.
Results
The primary analysis of seropositivity rates and GMTs was based on the ATP cohorts for
immunogenicity and included 556 subjects in the male cohort and 1,273 subjects in the female cohort,
vaccinated with Cervarix.
For both sexes and for both vaccine HPV-types, seroconversion rates of 100% were observed 1 month
after administration of the 3rd vaccine dose, in subjects that were seronegative at baseline (i.e. before
first vaccination). The data are presented in table 15. Seropositivity was defined as antibody titres ≥ 8
ELISA Units (EL.U) per mL for HPV-16 and ≥ 7 EL.U/mL for HPV-18.
Furthermore, in a descriptive analysis, GMTs for antibodies to the vaccine HPV-types are high in both
genders and comparable between the male and the female cohorts. Comparative data of the GMTs
(with 95% confidence intervals) in the two cohorts are also presented in Table 15.
Table 15. HPV-040 – Seropositivity rates and GMTs for anti-HPV-16/18 antibodies by gender in
subjects seronegative at baseline (ATP cohort for immunogenicity)
GMTs for anti-HPV-16 and HPV-18 antibodies by gender for subjects seronegative at baseline (ATP
cohort for immunogenicity) are presented in Figure 4.
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Figure 4. Month 7 GMTs with 95% CI for anti-HPV-16 and anti-HPV-18 antibodies by ELISA by gender
for subjects seronegative at baseline (ATP cohort for immunogenicity)
Results in the TVC were comparable to those seen in the ATP cohort for immunogenicity (not shown).
Irrespective of the pre-vaccination status of the subjects, the data indicate comparable
immunogenicity in males and females elicited by Cervarix, when administered according to a 0, 1, 6month schedule (not shown). Even though the comparison of immunogenicity between genders is
descriptive (statistically-powered inferential analyses was not planned per protocol), a large number of
subjects were included in this analysis, providing strong evidence of comparable immune responses to
the vaccine by both sexes. The data from study HPV-040 confirm the previous findings from study
HPV-011.
2.4.1.5. Supportive study
Study HPV-009 (post-hoc analysis)
HPV-009 is a randomised controlled (control: Hepatitis A vaccine) clinical efficacy Phase III trial in
women 15-25 years of age, including those with current or prior infection with oncogenic HPV. HPV009 was conducted in Costa Rica from 2004 to December 2010. See the table below for further details
on study design.
The final study results at 48 months were submitted as FUM 027 in June 2012 to provide clinical
efficacy data of Cervarix in the 3-dose schedule in the prevention of cervical lesions and cervical cancer
(advanced cervical intraepithelial neoplasia [CIN2, CIN3], adenocarcinoma in situ [AIS] and invasive
cervical cancer) associated with HPV-16 or HPV-18 cervical infection in healthy young adult women in
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Costa Rica. The FUM 027 submission enclosed a Clinical Overview and the Clinical Study Report at
completion of the study (from Month 6 to Month 48).
In addition, HPV-009 data investigating the potential benefit of vaccination in women with prevalent
infection with HPV-16 or HPV-18 were submitted within FUM 036 in June 2012. The CHMP concluded
that women with a prevalent HPV 16 and/or 18 infection do not benefit from protection from disease
caused by HPV types for which the subjects were HPV DNA positive at the time of the first vaccine dose
administration. Therefore the outcome of FUM036 had no impact on the Cervarix SmPC.
At the final blinded study visit 4 years after vaccination, a number of women were selected to provide
anal samples for assessment of vaccine efficacy against anal HPV-16/18 infection (Kreimer et al.,
Lancet Oncology 2011 1). The efficacy of vaccination against anal infection with HPV-16/18 was
estimated in two cohorts:
•
The full cohort included all vaccinated women who had given an anal sample and had HPV
results available. Thus, in this cohort, no exclusions were based on HPV-16/18 DNA positivity
or HPV-16/18 serostatus. The cohort included 193 subjects that were HPV-16/18 DNA positive
(at the cervix) before vaccination and 665 subjects that were HPV-16/18 seropositive before
vaccination (please refer to figure 1 in the publication reflecting an erratum published online by
The Lancet Oncology on October 28, 2011). Overall, at enrolment, 10% of subjects in the HPV
group were HPV-16/18 DNA positive and 39% were HPV-16/18 sero-positive.
•
The restricted cohort excluded women with evidence of prevalent cervical HPV-16/18 infection
(DNA) or HPV-16/18 antibodies before vaccination.
The following efficacies against anal HPV-16/18 infection were estimated in the two cohorts: 62.0%
(95% CI: 47.1, 73.1) in the full cohort and 83.6% (95% CI: 66.7, 92.8) in the restricted cohort.
Similar data of lower estimated efficacy in the full cohort versus the restricted cohort were observed in
the same study for cervical HPV-16/18 infection and for anal and cervical infection with the nonvaccine types HPV-31, HPV-33 and HPV-45 (exclusion of HPV-31, HPV-33 and HPV-45 DNA positive
individuals at time of vaccination from the restricted cohort). However, subjects seropositive for HPV31/33/45 were not excluded from the analysis as the serology was not performed at enrolment for
these types. The data are published in the same article (Kreimer, 2011). The data described by
Kreimer are in line with previous observations on the efficacy against cervical infection (Hildesheim,
2007; Szarewski, 2012), showing that vaccination did not impact the outcome of HPV infections
present at the time of vaccination. The latter study however shows that individuals with prevalent
infection with one HPV vaccine type at the time of vaccination, still benefit from the protection against
infection with the other vaccine HPV-type and cross reacting HPV-types. Of note, in the same trial at
baseline, less than 1% of the subjects were DNA positive for both HPV-16 and HPV-18, the main HPV
types associated with cervical cancer (Paavonen, 2009).
Inclusion of HPV-009 post-hoc data in the SmPC
The MAH proposed to include the Kreimer data in SmPC section 5.1 as HPV-009 data providing
evidence of vaccine efficacy against anal and cervical prevalent infection associated with HPV-16/18
and HPV-31/33/45. Further clarification and full data submission were requested to the MAH during the
current variation procedure. The MAH confirmed that the efficacy of Cervarix against anal HPV infection
associated with HPV-16/18 and HPV-31/33/45 has been evaluated by the National Cancer Institute
(NCI, US) as a HPV-009 post-hoc study. The NCI was the study Sponsor and the MAH was not involved
1
Kreimer AR, González P, Katki HA, Porras C, Schiffman M, Rodriguez AC, Solomon D, Jiménez S, Schiller JT, Lowy DR, van
Doorn LJ, Struijk L, Quint W, Chen S, Wacholder S, Hildesheim A, Herrero R; CVT Vaccine Group. Efficacy of a bivalent HPV
16/18 vaccine against anal HPV 16/18 infection among young women: a nested analysis within the Costa Rica Vaccine Trial.
Lancet Oncol. 2011;12(9):862-70.
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in the conduct of the study. Consequently, the MAH does not have rights on the study data and
materials and cannot develop a clinical study report. Nevertheless, in the view of the MAH, the data
published by Kreimer et al. are highly relevant to the prescriber, as they represent key evidence of the
vaccine efficacy against anal lesions.
The CHMP considered that an independent regulatory assessment of the study methodology including
the selection of subjects and the full statistical analysis plan is not possible. Moreover, Kreimer et al.
provides data on prevalent anal HPV infection at one time point i.e. 4 years post vaccination, but not
on persistent anal infection that lasts for at least 6 months. For the cervical indication, persistent
cervical infection that lasts for at least 6 months has been shown to be a relevant surrogate marker for
cervical cancer. Data on persistent infection are therefore considered to be a measure for vaccine
efficacy, and consequently are relevant for inclusion in the SmPC. Data on anal infection can be
included in the SmPC provided that they reflect persistent anal infection that lasts for at least 6
months. Since Kreimer et al. do not provide these data, the CHMP concluded that these data, although
encouraging, do not add important information in the SmPC.
Importantly, the MAH clarified that the NCI recently published the study design of the long term
follow-up study of the Costa Rica Vaccine Trial (CVT or HPV-009, NCT00128661). The study started
after completion of the CVT in 2010 and will provide 6 additional years of follow-up for a total of 10
years. One of the objectives is to assess the global impact of HPV vaccination in young adult women.
Persistent anal infection data are an expected outcome of the study (Gonzalez, 2015 2). The long-term
follow-up study is registered under clinicaltrial.gov as NCT00867464
(https://clinicaltrials.gov/ct2/show/study/NCT00867464). The Sponsor is the US NCI.
2.4.1.6. Additional analyses
Estimation of absolute benefit of preventing anal cancer and study on vaccine effectiveness
During the procedure, the MAH was requested to estimate the absolute benefit of Cervarix preventing
anal cancer in the general population by calculating the Number Needed to Vaccinate. As known, the
incidence of anal cancers is quite low and varies between 0.55 and 2.4/100,000 person-years in
women (Stier, 2015) and was estimated at 0.77/100,000 person-years in men (Faivre, 2012). The
incidence rate of High-grade Anal Intraepithelial Neoplasia (HGAIN) was estimated at 1.19/100,000
and 9.24/100,000 respectively for women and men (Simard, 2013). Consequently, the number needed
to vaccinate to prevent one anal cancer case, as calculated by the MAH, is relatively high (varying
between 2762 and 1105 in 12 year-old boys and between 2066 and 826 12 year-old boys and girls
depending on the vaccine effectiveness assumptions and the increase of the anal cancer incidence over
the remaining life span).
The MAH has also modelled the maximum plausible benefit in terms of number of any HPV-related
cancer cases avoided (including cervical, vulvar, vaginal, anal, penile and oropharyngeal cancers) in
the United Kingdom (UK). Several hypotheses were made such as a vaccine coverage of 86.8% was
applied (based on uptake figures for the HPV programme in England); the vaccine efficacy was
assumed to be the same for all HPV cancers as observed for cervical cancers; the vaccine effectiveness
was approximated by combining the vaccine efficacy with the Population Attributable Fraction for each
cancer. As a result of vaccinating boys and girls, 3,748 cancer cases due to HPV in women compared
with 1,043 cancer cases due to HPV in men could theoretically be prevented annually in the UK. These
estimates include 541 avoidable anal cancer cases in women compared with 294 avoided anal cancer
cases in men (ESPID Congress, 2014).
2
Gonzalez et al. Rationale and design of a long term follow-up study of women who did and did not receive HPV 16/18
vaccination in Guanacaste, Costa Rica. Vaccine 2015 Apr 27;33(18):2141-51.
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High risk populations like HIV infected, transplant recipients or MSM are more vulnerable to anal
infections and thus represent a more realistic potential population than the general population to
assess the vaccine effectiveness against anal cancers/lesions. The incidence rates of HGAIN vary
between 8.5 and 15.5/100 person-years in HIV-positive MSM and between 3.3 to 6.0/100
person/years in HIV-negative MSM (Machalek, 2012). In a high risk population of HIV-uninfected
adolescents, the rates of anal dysplasia were estimated at 2.7 and 13/100 person-years for girls and
boys aged between 12 to 18 years (Mullins, 2013). In terms of persistence of anal HPV infection, one
study has demonstrated that the 12-month persistence rate varies between 28% and 46% in HIV
infected (Beachler, 2013).
During the procedure, the MAH was requested to thoroughly assess the feasibility of conducting a postauthorisation vaccine effectiveness study to estimate the prevention of persistent infection, anal
lesions and anal cancer. The challenges as to the feasibility and bias of such study are acknowledged
(e.g. a large sample size of approximately 300,000 individuals; no routine screening programmes for
anal lesions are available which increases the difficulties of identifying cases or implementing a
surveillance programme). The assessment of the available registries and databases suggests that the
use of a large database like CPRD does not seem to be an adequate source of data for identifying anal
cancer or lesion cases (due to e.g. lack of detail coding for case identification and no information on
HPV type PCR testing, under-reporting of vaccination status, rarity of cases).
A prospective field data collection and a large sample size with a close (regular anal cytology and HPV
screening) and long-term follow-up of the disease would be required. The Cancer Registry in Sweden,
which collects AIN grade 3, would allow generating effectiveness data over time. However, the
Cervarix uptake in this country is quite low. This registry would allow generating effectiveness data
over time with qHPV. Therefore, it was considered highly relevant that the long-term impact of
Cervarix on anal HPV persistence is being monitored in the Cervarix-vaccinated Costa Rican cohort by
the US NCI, and this data should be submitted for review as they become available.
2.4.2. Discussion on clinical efficacy
Design and conduct of clinical studies
CSRs for studies HPV-10 and HPV-011 were already submitted in previous applications and assessed.
Design and conduct of the clinical studies presented in this submission are found acceptable by the
CHMP.
Immunogenicity data
In the present application, data in support of the indication of prevention of anal lesions and anal
cancer in males and females for Cervarix are submitted, based on a strategy of multiple
immunogenicity bridging i.e. between the two HPV-vaccines in the female population, and between the
male and female populations that received Cervarix.
The MAH demonstrated the potential clinical efficacy of Cervarix against anal lesions and anal cancer in
both males and females by:
•
In females: Immunogenicity bridging to another HPV vaccine that currently has the same
indication (anal lesions and anal cancer) based on efficacy data in males (qHPV);
•
In males: Immunogenicity bridging to a population in which vaccine efficacy in the indication
against cervical cancer and lesions has been demonstrated (females aged 15-25 years).
Immunogenicity bridging between qHPV and Cervarix in the male population was not performed.
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Table 16 provides an overview of the immunogenicity results and comparisons performed.
Table 16. Overview of immunobridging to support the anal indication application
Gender
Age
(years)
Comparison
Data
point
Cervarix
3-dose
M
F
10-18
Seroresponses rate, GMT
M7
●
12-15
GMT
M7
o
9-14
Seroresponses rate, GMT
M12
12-15
GMT
M7
o
15-25
Seroresponses rate, GMT
M7
●
18-45
Seroresponses rate, GMT
M60
x
qHPV
2-dose
3-dose
2-dose
xx
xx
xx
x
(x): Superior GMTs of Cervarix compared to qHPV in females aged 18-45 years in a 3-dose schedule up to Month
60 (HPV-010) and (xx): Non-inferior seroconversion rate of Cervarix compared to qHPV in females aged 9-14 in a
2-dose schedule up to Month 12 (HPV-071)
(●): Non-inferior immune response in males aged 10-18 years and females aged 15-25 years in a 3-dose schedule
of Cervarix at Month 7 (HPV-011).
(o): Similar GMTs in males and females aged 12-15 years in a 3-dose schedule of Cervarix at Month 7 (HPV-040).
Data in females
In study HPV-010 the primary superiority assessment was performed in the TVC (regardless of
serostatus and DNA status at baseline) and demonstrated superiority of the antibody titres in the
Cervarix group versus qHPV for all age groups (18-26 years; 27-35 years and 36-45 years) and for
both HPV-16 and HPV-18 at month 7 post-vaccination.
Final results up to Month 60 in females 18-45 years old who received 3-dose Cervarix showed that
antibody titres reached a peak response at Month 7, showed a decline up to Month 12 in all three
groups, and then remain relatively stable over time (kinetic cohort) and superior to 3-dose qHPV
regardless of baseline serostatus (TVC cohort), across the three age strata (table 2). Superiority
testing at subsequent time points after month 7 was done by exploratory inferential statistics.
HPV-071 compared Cervarix 2-dose vaccination vs. qHPV 2-dose vaccination in females aged 9-14
years of age, demonstrating at Month 7: i) non-inferiority in terms of seroconversion rates and GMTs
(ATP cohort); ii) superiority in terms of GMT ratio in the Total Vaccinated Cohort .
Subsequently this study showed that the immunogenicity (seroconversion and GMTs) of Cervarix
administered according to a 2-dose schedule at 0, 6 months was non-inferior/superior to that of qHPV
vaccine administered according to the standard 3-dose schedule (0, 2, 6 months) at Month 7 in the
ATP cohort. Superiority was also demonstrated on secondary objective for Cervarix 2-dose vs qHPV 3dose at Month 7 in the TVC cohort.
The same analyses were repeated as secondary objectives at Month 12, demonstrating non-inferiority
of Cervarix 2-dose immune response vs qHPV 2-dose or 3-dose in the ATP cohort. Superiority of the
immune response in terms of GMTs was also met at Month 12 in the TVC cohort for Cervarix 2-dose
vs. qHPV 2-dose and 3-dose.
Overall studies conducted in girls aged 9 to 14 years (study HPV-071) and in women aged 18 to 45
years (study HPV-010) have consistently shown a higher immune response with Cervarix (either noninferior or superior) than with the comparator for which efficacy data against anal premalignant lesions
are conclusive and have shown protection. Results shown by ELISA were confirmed by PBNA.
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Data in males
Study HPV-011 compared immunogenicity data from 3-dose Cervarix vaccination in males aged 10-18
years to immunogenicity data from 3-dose Cervarix vaccination in females aged 15-25 years from
study HPV-012 (the age range in which Cervarix clinical efficacy against cervical lesions and cancer
was demonstrated – studies HPV-001 and 008). At Month 7 in the ATP cohort, this inter-study
inferential analysis demonstrated non-inferiority in terms of seroconversion rates (100%) and GMT
ratios in males vs. females (22,600 vs. 7.300 for HPV16; 8,400 vs. 3,300 for HPV18). No post Month 7
immunogenicity data is available, which is a limitation to the presented comparison between males and
females.
Interim results from Study HPV-040 showed that comparable seroconversion rates (100%) and GMTs
at Month 7 (24,000 vs. 21,000 for HPV16 and 8,500 vs. 8,100 for HPV18) are achieved in the ATP
cohort after a 3-dose Cervarix vaccination in males aged 12-15 years compared to females aged 12-15
years, for both HPV 16 and 18 types.
The 2 studies in males compared immune response to the vaccine between genders overall
demonstrating similar immunogenicity of Cervarix in males versus females. The data indicate
comparable immunogenicity in males and females elicited by Cervarix, when administered according to
a 0, 1, 6-month schedule, even irrespective of the pre-vaccination status of the subjects (not shown).
Even though the comparison of immunogenicity between genders is descriptive (statistically-powered
inferential analyses was not planned per protocol), a large number of subjects were included in this
analysis, providing strong evidence of comparable immune responses to the vaccine by both sexes.
In summary, the basis of this application for an indication including anal cancers and premalignant
lesions for Cervarix is immunogenicity and safety data. Immune responses to Cervarix given either
according to a 2- or 3-dose schedule, as appropriate for each age group, were shown to be superior to
those of qHPV (HPV-011 and 071).
Efficacy data and additional analyses
No clinical efficacy data have been provided on the prevention of anal lesions or anal cancer by
Cervarix.
The MAH clarified that, due to the widespread and/or recommended use and global licensure of qHPV
for the prevention of anal lesions and anal cancer (without gender restriction), the conduct of a
placebo controlled efficacy trial for Cervarix might potentially raise ethical concerns since a potentially
efficacious vaccine would be withheld from the placebo group (Reflection Paper on ethical and GCP
aspects of clinical trials of human medicinal products conducted outside the EU/EEA and submitted in
MAA to the EU regulatory authorities (EMA/121340/2011)). On the other hand, the conduct of an
active-controlled efficacy trial would not be feasible due to the high efficacy demonstrated by qHPV
against AIN (78.6% [95% CI: -0.4-97.7] against HPV-16/18 in the per-protocol cohort) and persistent
anal infection (95.8% [95% CI: 74.1-99.9] against HPV-16/18 in the per-protocol cohort] in the MSM
study (Palefsky, 2011). In addition, HPV-related anal lesions and cancers are rare diseases
(approximately 27,000 new cases per year globally, of which about 24,000 are HPV-related (de Martel,
2012) or approximately 0.1 to 2.8 cases per 100,000 among men and 0.0 to 2.2 per 100,000 among
women (Hoots, 2009)). A clinical trial to assess the efficacy of Cervarix against anal lesions and cancer
development would therefore require a very large sample size and would take many years to
complete. This rationale is in line with the CHMP guideline on the clinical evaluation of new vaccines
(EMEA/CHMP/VWP/164653/05), which recommends estimating the relative protective efficacy of a
candidate vaccine by comparing it with a licensed vaccine that protects against the same infection,
recognising that, in such a context, estimating protective efficacy may indeed not be feasible.
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The CHMP agreed to the immunobridging strategy and considered that sufficient evidence based on
immunological comparison has been provided to reasonably estimate Cervarix efficacy against anal
lesions an anal cancer.
The post-hoc data on Cervarix efficacy against anal HPV infection published by Kreimer et al., which
uses incident infection measured at one time point only as opposed to persistent infection, is not in
itself supporting an indication of prevention of anal lesions, although the results of incident infection
are encouraging 62.0% (95% CI: 47.1, 73.1) in the full non-naïve cohort and 83.6% (95% CI: 66.7,
92.8) in the restricted naïve cohort). The data described by Kreimer et al. are in line with previous
observations on the efficacy against cervical infection showing that vaccination did not impact the
outcome of cervical HPV infections present at the time of vaccination. Hence Cervarix is preferably
administered to individuals as of 9 years of age, before sexual debut, to get full benefit of HPV
vaccination. Data on anal HPV infections were not collected at baseline, but anal infection at baseline is
anticipated to be in line with cervical infection at baseline. The data on protection against anal infection
should not be included in the SmPC, as this is not an agreed surrogate marker for anal cancer or
precancerous lesions. The data on persistent anal infection are an expected outcome of the Kremer
follow up study, and are considered highly relevant and should be submitted for review a soon as
available. However they are not considered necessary to approve the current application, based on the
evidence available.
The absolute benefit of Cervarix preventing anal cancer in the general population was estimated by
calculating the Number Needed to Vaccinate. These assumptions are not intended nor required in order
to corroborate the evidence provided in support of the anal cancer indication for Cervarix; they show
however that a substantial number of anal cancer cases could be avoided in the general population
and, more specifically, in the male population by vaccinating individuals with Cervarix.
2.4.3. Conclusions on the clinical efficacy
A large proportion of anal lesions and cancer cases are associated with HPV, predominantly types 16
and 18. Prophylactic vaccination against these oncogenic HPV types and as such prevention of the
disease represents a cornerstone among available medical approaches.
The basis of this application for an indication including anal cancers and premalignant lesions for
Cervarix is immunogenicity and safety data. Immune responses to Cervarix given according to a 2- or
3-dose schedule based on age were shown to be superior to those of qHPV, which is approved for the
prevention of anal cancers and premalignant lesions, based on efficacy against AIN 2/3 related to HPV
16/18 in MSM and based on immunological bridging to younger age groups of boys. Immunogenicity
bridging has been indeed found acceptable before as the basis of inferring clinical efficacy of HPV
vaccines in younger age groups based on demonstrated vaccine efficacy in older age groups. It is
therefore considered reasonable to accept immunobridging data in support of an indication against
anal lesions for Cervarix. Considering that the immune responses to Cervarix, generally are higher
compared to qHPV in the comparative studies available, the expected benefit from Cervarix vaccination
against anal lesions and cancers in a male and female population is considered similar to qHPV and
acceptable for licensure.
For this application, it was considered that further investigations of Cervarix efficacy against clinical
efficacy endpoints (persistent infection, high grade anal lesions and anal cancer) were not considered
feasible. This rationale, in line with current guidelines, was found acceptable by the CHMP.
Efficacy of Cervarix against anal infection with HPV types 16 and 18, which is the first necessary step
of the pathogenic process for HPV-16/18 related anal lesion and cancer, was shown in a post-hoc study
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by Kreimer et al. following the HPV-009 Costa Rica vaccine trial. Analyses on persistent anal infection
are ongoing.
The CHMP considers that it would be relevant to follow-up on such analyses, and thus recommends the
following measure, to which the MAH agreed:
Submit as soon as available the efficacy results on persistent anal infection in women 15-25 years of
age, which are an expected outcome of the Kremer follow up post-hoc study to study HPV-009
(Kreimer et al., Lancet Oncology 2011).
2.5. Clinical safety
Introduction
In the total Cervarix clinical development studies that enrolled girls and women aged from 10 up to 72
years (of which 79.2% were aged 10-25 years at the time of enrolment), Cervarix was administered to
16,142 females whilst 13,811 females received control. These subjects were followed for serious
adverse events over the entire study period. In a pre-defined subset of subjects (Cervarix 8,130 vs.
control 5,786), adverse events were followed for 30 days after each injection. Safety data in male was
not required for inclusion in the SmPC prior to this application.
The most common adverse reaction observed after vaccine administration was injection site pain which
occurred after 78% of all doses. The majority of these reactions were of mild to moderate severity and
were not long lasting.
Studies HPV-010 and HPV-071 were designed to compare the immunogenicity of Cervarix versus qHPV
in healthy adult females. In both studies, safety and reactogenicity were assessed as secondary
objectives. The results of study HPV-010 are already reflected in the SmPC. The safety of Cervarix for
administration in females is well documented through clinical trials and its commercial use. The
following sections will therefore focus on the safety and reactogenicity assessment of the
administration of Cervarix in male subjects, documented as secondary objectives in studies HPV-011
and HPV-040 (HPV-011: 10-18 years of age; HPV-040: 12-15 years of age). In both studies, GSK
Biologicals hepatitis B vaccine Engerix B1 was used as control.
Patient exposure
The safety and reactogenicity assessment of the administration of Cervarix in male subjects,
documented as secondary objectives in studies HPV-011 and HPV-040 (HPV-011: 10-18 years of age;
HPV-040: 12-15 years of age) are presented below. In both studies, GSK Biologicals hepatitis B
vaccine Engerix B was used as control.
The total number of male subjects that received at least one Cervarix vaccination in the two trials
concerned is 2,621 (181 subjects in study HPV-011 and 2,440 subjects in study HPV-040, see table
17).
For study HPV-040, passive surveillance will be performed in all study participants, up to the moment
they reach the age of 18.5 years. Active surveillance using diary cards was performed in a subset of
1,690 male subjects (out of 32,176 subjects representing the TVC), from Arm A and Arm C
communities, of which 643 in the Cervarix group. This subset of 1690 male subjects is referred to as
the “Diary Card subset” in the ensuing sections of the current document. The number of male subjects
in the Cervarix group with active safety follow-up for SAE up to Month 12 was 2,436.
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Table 17. Number of subjects who received at least one dose of Cervarix vaccine or control and total
number of doses administered in all studies
Studies
HBV
Cervarix
HPV-011
HPV-040
Number of subjects
who received at least
one dose of Cervarix
181 (males)
Number of doses
administered
14,838
2,440 males
12,398 females
44,331*
535
Number of subjects
who received at least
one dose of HBV
89 (males)
Number of doses administered
17,338
9,221 males
8,117 females
51,789*
262
HBV: Hepatitis B vaccine (Engerix B), control
*Compliance to the 3-dose schedule was 99.2% for both treatment groups
Study HPV-011
Endpoints
The safety endpoints analysed in study HPV-011 were:
•
Occurrence, intensity and causal relationship to vaccination of solicited general symptoms and
solicited local symptoms within 7 days (Days 0 - 6) after each and any vaccination.
•
Occurrence, intensity and causal relationship to vaccination of unsolicited symptoms within 30
days (Days 0-29) after any vaccination.
•
Occurrence of New Onset Chronic Diseases (NOCDs) and other medically significant conditions
throughout the study period (up to Month 7) regardless of causal relationship to vaccination
and intensity.
•
Occurrence of clinically relevant abnormalities in biochemical and haematological parameters
assessed at Day 0, Month 2 and Month 7.
•
Occurrence of severe adverse events (SAEs) throughout the entire study period (up to Month
7).
•
Occurrence of SAEs, NOCDs and other medically significant conditions from Month 7 through to
the Month 12 telephone contact.
Solicited local adverse events
During the 7-day (Days 0-6) post-vaccination period following each dose, in the TVC, pain was the
most frequently reported local solicited symptom. Pain was reported following 72.3% (68.2; 76.1) of
doses in the Cervarix group and following 22% (17.1; 27.6) of doses in the HBV group. Grade 3 pain
was reported after 1.9% (0.9, 3.5) of the doses in the Cervarix group and 0% (0.0; 1.4) in the HBV
group. Swelling at the injection site was reported in the Cervarix group following 10.7% (8.2; 13.7) of
doses compared to 3.1% (1.3; 6.0) of doses in the HBV group. Redness at the injection site was
reported in the Cervarix group following 16.6% (13.5; 20.1) of doses compared to 11.2% (7.6; 15.7)
of doses in the HBV group. The rate of reporting for redness and swelling was much lower than for
pain.
Solicited general adverse events
During the 7-day (Days 0-6) post-vaccination period following each dose (TVC), the most frequently
reported solicited general symptom was myalgia in the Cervarix group following 27% (23.2; 31.0) of
doses, and following 12.4% (8.6; 17.0) of doses in the HBV group. Grade 3 myalgia was reported
following 0.6% (0.1; 1.7) of doses in Cervarix group and following 0% (0.0; 1.4) of doses in HBV
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group. Myalgia possibly related to vaccination was reported following 20.5% (17.1; 24.2) of the doses
in Cervarix group and 7.7% (4.8; 11.7) in HBV group.
For the other solicited general adverse events, reporting frequency was lower. Arthralgia possibly
related to vaccination was reported following 4.8% (3.1; 7.0) of the doses in Cervarix group and 2.3%
(0.9; 5.0) in HBV group. Fatigue possibly related to vaccination was reported following 14.7% (11.8;
18.1) of the doses in Cervarix group and 14.7 % (10.6; 19.6) in HBV group. Fever possibly related to
vaccination was reported following 0.6 % (0.1; 1.7) of the doses in Cervarix group and 0.4% (0.0;
2.0) in HBV group. Gastrointestinal possibly related to vaccination was reported following 5.7% (3.9;
8.1) of the doses in Cervarix group and 3.5% (1.6; 6.5) in HBV group. Headache possibly related to
vaccination was reported following 10.5% (8.0; 13.5) of the doses in Cervarix group and 8.5% (5.4;
12.6) in HBV group. Rash possibly related to vaccination was reported following 1.1% (0.4; 2.5) of the
doses in Cervarix group and 0.4% (0.0; 2.1) in HBV group. Urticaria possibly related to vaccination
was reported following 0.2% (0.0; 1.1) of the doses in Cervarix group and 0.0% (0.0; 1.4) in HBV
group.
Unsolicited adverse events
The number of doses followed by at least one unsolicited symptom reported within the 30-day (Days
0-29) post-vaccination period was 15.7% (12.7; 19.1) in the Cervarix group and 15.6% (11.5; 20.6)
of doses in the HBV group. At least one unsolicited symptom was reported by 37.6% (30.5; 45.1) of
subjects in the Cervarix group and by 34.8% (25.0; 45.7) of subjects in the HBV group.
The most frequently reported symptoms were headache (following 3.2% (1.9; 5.0) and 3.8% (1.8;
6.9) of doses in Cervarix and HBV group, respectively), nasopharyngitis (following 2.4% (1.3; 4.1)
and 1.1% (0.2; 3.3) of doses in Cervarix and HBV group, respectively) and pharyngolaryngeal pain
(following 1.7% (0.8; 3.2) and 1.1% (0.2; 3.3) of the doses in Cervarix and HBV group, respectively).
With respect to these two latter events, the company considers that they are covered by the term
“upper respiratory tract infections” that is reported as an uncommon side effect in the label
information.
Grade 3 unsolicited symptoms were reported following 0.9% (0.3; 2.2) of doses in the Cervarix group
and 0.8% (0.1; 2.7) of doses in the HBV group. Unsolicited signs and symptoms with causal
relationship to vaccination were reported after 1.1% (0.4; 2.4) and 0.4% (0.0; 2.1) of the doses in the
Cervarix and the HBV group, respectively.
Serious adverse events
There were no fatal SAEs reported.
Two serious adverse events (Crohn’s disease and epilepsy) were reported during the active phase of
the study (i.e. up to Month 7), both in the Cervarix group (representing 1.1% (0.1; 3.9) of subjects),
but neither of them was assessed by the investigator as related to vaccination.
During the Month 7 to Month 12 safety follow-up, two serious adverse events were reported
(appendicitis in the Cervarix group (0.6% (0.0; 3.1) of subjects), osteochondrosis in the HBV group
(0.6% (0.0; 3.1) of subjects)). None of them were considered by the investigator as possibly related to
the vaccination.
New onset chronic diseases (NOCD)
During the active phase of the study (i.e. up to Month 7), three events were reported and determined
by a GSK physician (GSK assessment) as NOCDs, two in the Cervarix group (Crohn’s disease and
atopic dermatitis) and one in the HBV group (asthma). Crohn’s disease was also considered a NOAD.
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None of these events were assessed as possibly related to vaccination in the opinion of the
investigator. According to the investigators’ assessment, none of the events reported during the active
phase of the study were considered to be NOCDs.
No NOCDs were reported during the Month 7 to Month 12 extended safety follow-up period.
Medically significant conditions
Medically significant conditions were recorded during the active phase of the study (i.e. up to Month 7)
in the two groups (12.2% (7.8; 17.8) in the Cervarix group and 11.2% (5.5; 19.7) in the HBV group).
Three subjects experienced a medically significant condition during the extended safety follow-up
period: one subject in the Cervarix group (depression) and two subjects in the HBV group (herpes
zoster and osteochondrosis). None of them were considered to be related to study vaccination.
One subject (in the Cervarix group) was withdrawn from the study due to an adverse event (panic
reaction) following the first dose of vaccine and subsequent doses were not administered.
Haematological and biochemical assessment
No clinically relevant differences were observed in haematological and biochemical analyses at Month 2
or Month 7 as compared to the control.
Study HPV-040
Endpoints
Passive safety surveillance was performed in all communities based on a national health registry.
The following secondary safety endpoints were evaluated at the time of the submitted interim analysis:
1. Active safety surveillance was performed in all males from Arm A and Arm C communities
(Diary Card subset) until Month 12 as follows:
•
Males included in the Diary Card subset:
-
Solicited (local and general) signs and symptoms within 7 days (Days 0 - 6) after each
vaccination;
•
-
Unsolicited adverse events (AEs) within 30 days (Days 0- 29) after each vaccination;
-
Occurrence of rash and urticaria within 30 minutes following each vaccination;
-
Occurrence of medically significant conditions between Month 0 and Month 12;
-
Occurrence of SAEs between Month 0 and Month 12.
Male study participants from Arm A communities who were not included in the Diary Card
subset:
-
Occurrence of SAEs between Month 0 and Month 12.
2. Passive safety surveillance was performed in all study participants from all communities (Arms
A, B, C) starting from Dose 1.
3. Spontaneous reporting:
•
Any SAEs reported to the investigator and considered by the investigator as possibly related to
vaccination were reported to GSK Biologicals.
Solicited local adverse events
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During the 7-day post-vaccination period, pain at the injection site was the most frequent solicited
local symptom in both groups (reported after 70.4% (68.1; 72.7) and 14.0% (12.7; 15.4) of doses in
the Cervarix and HBV groups, respectively). Pain assessed as grade 3 in intensity was reported
following 2.0% (1.4; 2.8) and 0.1% (0.0; 0.3) of doses in the respective groups.
Solicited general adverse events
Of the solicited general symptoms during the 7-day post-vaccination period, fatigue (following 31.1%
(28.8; 33.4) and 21.5% (20.0; 23.1) of doses in Cervarix and HBV groups, respectively), headache
(following 23.9% (21.8; 26.0) and 18.8% (17.4; 20.3) of doses in Cervarix and HBV groups,
respectively) and myalgia (following 33.8% (31.5; 36.2) and 12.5% (11.3; 13.8) of doses in Cervarix
and HBV groups, respectively) were the most frequent in both groups. Solicited general symptoms
assessed as grade 3 in intensity were reported following at most 1.1% of doses in the Cervarix group
and 0.8% of doses in the HBV group. Solicited general symptoms with causal relationship to
vaccination were reported after 45.2% (42.7; 47.7) and 30.1% (28.4; 31.9) of the doses in Cervarix
and HBV groups, respectively.
Unsolicited adverse events
At least one unsolicited symptom was reported after 10.1% (8.8; 11.6) of doses in the Cervarix and
7.6% (6.7; 8.6) of doses in the HBV group during the 30-day post-vaccination period. Grade 3
unsolicited symptoms were reported following 1.6% and 1.5% of doses in the Cervarix and HBV
groups, respectively.
Unsolicited AEs considered by the investigator to be possibly related to vaccination were reported after
0.7% (0.4; 1.2) and 0.6% (0.4; 1.0) of doses in the respective groups.
Medically significant conditions (MSCs)
Medically significant conditions were reported for 7.3% (5.4; 9.6) and 7.3% (5.8; 9.0) of subjects in
Cervarix and HBV group, respectively, from dose 1 to Month 12 in the Diary Card subset. Three
subjects in the Cervarix group (0.5%) and one subject in HBV group (0.1%) reported each one
medically significant condition considered as possibly related to vaccination by the investigator
(including concussion, type 1 diabetes mellitus, juvenile arthritis and oropharyngeal pain; blinded to
treatment allocation). Type 1 diabetes mellitus and juvenile arthritis were reported and considered as
possibly related to the treatment by the investigator (blinded to treatment group). Both were also
reported as a NOAD. Overall events reporting rate was similar between test and comparator. Incidence
rates for the specific events were lower than the comparator.
Serious adverse events (SAE)
Within the full male population with active safety surveillance, SAEs were reported for 2.4% (1.8; 3.1)
of subjects in the Cervarix group and 2.0% (1.3; 2.9) of subjects in the HBV group. For four subjects
in the Cervarix group (0.2%) and one subject in the HBV group (0.1%), the SAEs were considered as
possibly related to vaccination according to the investigator (i.e., abdominal pain, colitis ulcerative,
type 1 diabetes mellitus and juvenile arthritis; blinded to treatment allocation). No fatal SAEs were
reported. For the administration of the vaccine in males, there seemed to be no difference between
groups and the reported rate of SAE after Cervarix vaccination within the male population is
comparable to that within the female population (Descamps, 2009).
New onset autoimmune disease (NOAD) (passive safety surveillance)
Within the 12-month post-vaccination period (i.e. from Dose 1 up to 12 months after the last vaccine
dose), the most common NOADs in female study participants were juvenile arthritis, colitis ulcerative,
coeliac disease, autoimmune thyroiditis, type 1 diabetes mellitus and idiopathic thrombocytopenic
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purpura, in addition to uveitis (three cases blinded to treatment allocation). In male study participants,
the most common NOADs were juvenile arthritis, colitis ulcerative and type 1 diabetes mellitus, in
addition to Crohn’s disease and coeliac disease (blinded to treatment allocation). No differences in the
nature of the NOADs were observed between males and females.
Post-marketing experience
Cervarix was first registered in 2007 and the vaccine is currently licensed for use in more than 130
countries worldwide. 44,176,610 doses have been distributed since registration (data lock point 31
October 2013). As Cervarix was a 3-dose vaccine until end of 2013, post-marketing exposure to
Cervarix since launch until 31 October 2013 is estimated as being between 14,725,537 and
44,176,610 subjects.
2.5.1. Discussion on clinical safety
Studies HPV-010 and HPV-071 submitted for this application were designed to compare the
immunogenicity of Cervarix versus qHPV in healthy adult females. In both studies, safety and
reactogenicity were assessed as secondary objectives. The results of study HPV-010 are already
reflected in the SmPC. The safety of Cervarix for administration in females is well documented through
clinical trials and its commercial use. The safety and reactogenicity assessment has therefore focused
on the administration of Cervarix in male subjects, documented as secondary objectives in studies
HPV-011 and HPV-040 (HPV-011: 10-18 years of age; HPV-040: 12-15 years of age). In both studies,
GSK Biologicals hepatitis B vaccine Engerix B1 was used as control.
Safety data for Cervarix vaccination in males originate from a population of 2,617 subjects (181
subjects in HPV-011 and 2,436 subjects with active safety follow-up in HPV-040) within the 10 to 18
years age range, immunised with at least one dose of the product. Of note, no statistically significant
comparative analysis has been performed between treatment groups. Therefore, any difference in the
data between treatment groups or genders needs to be interpreted with caution.
Within the 10 to 18 years of age group (study HPV-011) and in line with previous observations in other
studies conducted in females, the safety and reactogenicity profile of Cervarix seemed comparable to
that of the control vaccine, with the exception of local solicited symptoms and myalgia. Local
symptoms and myalgia seemed to be more frequent in the Cervarix group. The apparently higher rate
of solicited symptoms did not negatively impact the acceptance of the vaccination, as 97% of both
study groups in study HPV-011 completed the 3 dose vaccination schedule. Together with the overall
low percentage of grade 3 symptoms (solicited and unsolicited) during the 30-day post-vaccination,
which seemed comparable between the two treatment groups, these data indicate that the Cervarix
vaccine is generally well tolerated in the male population.
In the larger set of subjects within the 12 to 15 years of age range (2,440 male subjects; HPV-040),
the same conclusion can be drawn. Whereas the results suggested a higher frequency of local solicited
symptoms (e.g. pain) in the Cervarix group as compared to the control group, reported as part of the
active surveillance, the frequency of solicited general symptoms was lower as compared to the local
symptoms and the potential difference between the treatment groups was less pronounced. The most
frequently reported general symptoms are fatigue, headache and myalgia, which are already
mentioned in the current label of the vaccine as very common symptoms. The percentage of these
symptoms considered by the investigator as possibly related to vaccination seemed comparable
between the groups.
For the administration of the vaccine in males, SAE rate was within the rate observed for female
population, which is already approved. Also, no differences in the nature of the NOADs were observed
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between males and females. In addition, overall SAEs reporting rate was similar between Cervarix and
comparator. The incidence rates for the specific events were lower than the comparator. In any case,
concerning NOADs, since the ‘Theoretical risk of acquiring vaccine-induced autoimmune disease after
vaccination’ is part of the safety concerns in the RMP and is categorised as an important potential risk,
auto-immune mediated diseases (AIDs) incidence in vaccinees and link to vaccination are closely
monitored and reported in the PBRER/PSUR.
There are no data of Cervarix use in populations with high risk for HPV infection such as
immunosuppressed patients.
Cervarix safety profile has been further evaluated in another Type II variation
(EMEA/H/C/000721/II/0069) relating to risk for auto-immune diseases with Cervarix, which was
ongoing in parallel to this procedure. Variation II/69 considered the following evidence:
1. a Post-Authorization Safety Study, EPI-HPV-040, investigating a potential risk of immune
disorder linked to Cervarix vaccination in an adolescent and young adult population (results of
observed versus expected analysis in post-marketing surveillance). Based on the results, the
PRAC agreed that the data generated did not require an update of the current SmPC, since the
results are either negative for the auto-immune disorders studied (e.g. for GBS) or
inconclusive, particularly concerning auto-immune thyroiditis.
2. Best quality evidence from randomized controlled trials, in which the pooled analysis and the
meta-analysis do not show an increased risk of autoimmune thyroiditis; data from other
pharmacoepidemiological studies, which were powered to detect a risk of combined
autoimmune diseases, show conflicting results but the observed incidence rates of autoimmune
thyroiditis seems in line with background rates reported in the literature.
3. the results of a large pharmaco-epidemiological study performed by the ANSM in France were
published online: http://ansm.sante.fr/S-informer/Points-d-information-Points-dinformation/Vaccination-contre-les-infections-a-HPV-et-risque-de-maladies-auto-immunesune-etude-Cnamts-ANSM-rassurante-Point-d-information. The study investigated the incidence
of auto-immune diseases in 2,256,716 girls (mean age at inclusion: 13.5 years), of whom
842,120 (33%) had been delivered at least one dose of anti-HPV vaccine during follow-up
(qHPV: 93%; Cervarix: 7%). No overall increase in the risk of onset of auto-immune disease
was observed in subjects after exposure to at least one dose of anti-HPV vaccine compared to
those not exposed. However, the authors reported a significant association with HPV
vaccination for inflammatory bowel disease (IBD) and Guillain-Barre syndrome (GBS). Due to
the limitations of this study and the small numbers of events, these results should be
interpreted with caution.
Overall based on the data shown in variation II-69 an update of the SmPC was not deemed necessary.
The PRAC requested the MAH to provide updates on autoimmune thyroiditis diseases and GBS in the
following PSURs.
Concerning this application, although discrepant reports are available in the literature, a slightly higher
background incidence of GBS has been reported in males compared to females, at all age categories,
in a systematic review and meta-analysis of published studies reporting GBS incidence to obtain
estimates of population based age-specific incidence of GBS in North America and Europe 3 (with agespecific incidence rates estimated at 0.97/100,000 p-y in 10-19 year-old and 1.18/100,000 p-y in 203
Shui IM, Rett MD, Weintraub E, Marcy M, Amato AA, Sheikh SI et al. Guillain-Barré Syndrome incidence in a large United
States cohort (2000-2009). Neuroepidemiology 2012;39:109-115.
Sejvar JJ, Baughman AL, Wise M, Morgan OW. Population incidence of Guillain-Barré syndrome: a systematic review and
meta-analysis. Neuroepidemiology. 2011;36(2):123-133.
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29 year old for males versus 0.55 and 0.66/100,000 p-y in 10-19 year-old and in 20-29 year-old
females, respectively). Based on these data, a gender-specific higher risk of developing GBS cannot be
ruled out. However nothing is known about the risk following male immunization. Considering that
Cervarix up until now does not have an indication in males, the available safety data from large
epidemiological studies would include women only. Until such studies are available including males too,
there is no evidence to suggest that the risk of autoimmune diseases following vaccination would differ
substantially between genders.
The MAH proposed a meta-analysis (Study EPI-HPV-069) that will focus primarily on data obtained in
females, and will therefore be of limited interest for the male population. Nevertheless, its value in
terms of risk assessment is acknowledged. Such meta-analysis is intended to investigate the potential
association of Cervarix vaccination and the risk of developing autoimmune thyroiditis, GBS and
inflammatory bowel diseases.
All the evidences available to GSK arising from clinical trials, literature and epidemiological studies will
be included in this assessment.
Further investigation on the data published by the French authorities is also planned. The RMP has
been updated according to this information during the course of this procedure and in the PBRER/PSUR
assessment procedure that was ongoing in parallel (versions 16.1 and 16.2).
2.5.2. Conclusions on clinical safety
The data from studies HPV-011 and HPV-040 demonstrate that Cervarix vaccination is well tolerated in
the male population and that the vaccination of boys/men elicits similar antibody titres in the
boys/men as compared to girls/women. No safety signals or adverse events differing from the safety
profile of Cervarix observed in vaccinated females have so far been reported in males.
Taken together, the safety results from the two studies HPV-011 and HPV-040 indicate that
administration of Cervarix is generally well tolerated in males within the range of 10 to 18 years of
age. Overall, the safety profile in men is similar to that in women and is in line with the currently
approved label. Therefore, the CHMP agrees to include vaccination of males as of 9 years of age in the
Cervarix SmPC, in line with the currently indicated age range for women.
The theoretical risk of acquiring an autoimmune disease following vaccination is raised by the
immunological action mechanism of vaccines. This important potential risk is identified for both males
and females, although most autoimmune diseases disproportionally affect females. The RMP was
updated to reflect the risk in males.
Multiple studies have been performed to assess the risk of autoimmune thyroiditis disease and GBS
following HPV vaccination resulting, in some cases, to contrasting results (e.g. EPI-HPV-011 4, EPI-HPV040, pharmacoepidemiological French study, pooling of clinical data). To address these findings, the
MAH will further investigate the potential association of Cervarix vaccination and the risk of developing
autoimmune thyroiditis diseases, GBS and inflammatory bowel diseases by conducting a meta-analysis
of all available data from company’s studies as well as any published studies performed by third
parties (Study EPI-HPV-069). Potential immune-mediated diseases (pIMDs) are also followed up in
PSURs.
4
EPI-HPV-011 is a long-term safety surveillance of Cervarix in France assessing incidence of autoimmune diseases
following Cervarix in young adult women. The objective of the study started in 2008 was to assess whether the use of
Cervarix was associated with a modified risk of demyelination, type 1 diabetes, cutaneous lupus, inflammatory arthritis,
idiopathic thrombocytopenic purpura, lupus erythematosus, myositis and dermatomyositis, Guillain-Barre syndrome, and
autoimmune thyroiditis and Graves’ disease.
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2.5.3. PSUR cycle
The PSUR cycle remains unchanged.
The next data lock point will be 17 November 2016.
The annex II related to the PSUR, refers to the EURD list which remains unchanged.
2.6. Risk management plan
The PRAC considered that the risk management plan version 16.0 could be acceptable if the MAH
implements the changes to the RMP as described in the PRAC endorsed PRAC Rapporteur assessment
report.
The MAH implemented the changes in the RMP as requested by PRAC, and has also included the
changes in RMP version 15, as agreed during the parallel PSUSA assessment.
The CHMP endorsed the Risk Management Plan version 17 with the following content:
Safety concerns
Summary of safety concerns
Important identified
None identified
risks
Important potential
Theoretical risk of acquiring vaccine-induced autoimmune disease
risks
after vaccination
Missing information
Use of HPV-16/18 vaccine in HIV-infected subjects or subjects with
known immune deficiencies
Impact of HPV-16/18 vaccine in pregnant women who are
inadvertently exposed to the vaccine
HPV type replacement
Impact and effectiveness against anal lesions and cancer
Pharmacovigilance plan
Study/activity Type, title and
category (1-3)
Objectives
Safety
concerns
addressed
Status
(planned,
started)
Study HPV-019
A phase I/II, partially-blind,
randomized, controlled study to
assess the safety and
immunogenicity of
GlaxoSmithKline Biologicals’ HPV16/18 vaccine administered
intramuscularly according to a
three-dose schedule (0, 1, 6month) in human
immunodeficiency virus (HIV)infected female subjects aged 1825 years.
(Category 3)
Safety and
immunogenicity in
HIV-positive women
Missing
information:
use in HIVpositive
subjects
Study
started
Study HPV-039
A phase II/III, double-blind,
randomized, controlled study to
evaluate the efficacy,
immunogenicity and safety of
GlaxoSmithKline Biologicals’ HPV16/18 L1 VLP AS04 vaccine,
Safety,
immunogenicity and
efficacy in Chinese
female subjects
Potential risk
of
autoimmune
diseases,
Missing
information:
(Pregnancy
Study
started
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Date for
submission of
interim or final
reports (planned
or actual)
Month 24 study
results were
anticipated to be
available by June
2014, but as the
enrolment took
longer than
anticipated, results
will be available at
a later date
(estimated March
2018).
End of study report
December 2016
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Study/activity Type, title and
category (1-3)
Objectives
administered intramuscularly
according to a 0, 1, 6-month
schedule in healthy Chinese
female subjects aged 18-25 years.
(Category 3)
Safety
concerns
addressed
Status
(planned,
started)
Date for
submission of
interim or final
reports (planned
or actual)
and
pregnancy
outcome)
Study HPV-040
A phase III/IV, communityrandomized, controlled study to
evaluate the effectiveness of two
vaccination strategies using
GlaxoSmithKline Biologicals’ HPV16/18 L1 VLP AS04 vaccine in
reducing the prevalence of HPV16/18 infection when administered
intramuscularly according to a 0,
1, 6-month schedule in healthy
female and male study
participants aged 12 – 15 years.
(Category 3)
Effectiveness of two
vaccination strategies
in reducing the
prevalence of HPV16/18 infection in
healthy female and
male subjects.
Potential risk
of
autoimmune
diseases,
Missing
information:
(Pregnancy
and
pregnancy
outcome),
Study
started
Final study report
June 2016
EPI-HPV-048 (Category 3)
Surveillance study (follow-up of
the EPI-HPV-033) of type-specific
HPV infections among women in
England to 2016.
In addition, surveillance of typespecific HPV in cervical cancers in
women under 30 years old.
Type-specific
surveillance among
sexually active
females who have
been offered HPV
vaccination, to
demonstrate vaccine
effectiveness against
vaccine and nonvaccine types (i.e.
type replacement)
HPV type
replacement
Planned
2nd quarter 2019
EPI-HPV-069 (Category 3)
A meta-analysis using all available
data from company’s studies as
well as published studies
performed outside.
To assessing the
potential association
of Cervarix vaccination
and the risk of
developing
autoimmune
thyroiditis by
providing an overall
estimate of the
relative risk of
autoimmune
thyroiditis following
Cervarix vaccination.
Potential risk
of
autoimmune
thyroiditis
Study
started
September2016
Post-Marketing Surveillance
Activity (Category 3):
Monitoring of annual reporting of
anal cancer and other HPV-related
cancer by consulting 5 national
cancer registries (Finland, The
Netherlands, UK, Norway and
Denmark)
To collect data for the
quinquennial trend
analysis of the
occurrence of anal
cancer and other HPVrelated cancers
Missing
information:
Impact and
effectiveness
against anal
lesions and
cancer
Planned
December 2016
Post-Marketing Surveillance
Activity (Category 3): Trend
analysis of anal cancer and other
HPV-related cancer every 5 years
To describe the
potential changes over
time in the occurrence
of anal cancer and
other HPV-related
cancers in countries
where Cervarix is
used.
Missing
information:
Impact and
effectiveness
against anal
lesions and
cancer
Planned
December 2021
(submitted with
next cyclical
PBRER).
Post-Marketing Surveillance
Activity (Category 3): Feasibility
assessment to perform a casecontrol study to assess the
Re-assess the
feasibility of an
effectiveness/impact
study of Cervarix
Missing
information:
Impact and
effectiveness
Planned
December 2021
(submitted with
next cyclical
PBRER).
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Study/activity Type, title and
category (1-3)
Objectives
Safety
concerns
addressed
effectiveness and /or impact of
HPV vaccination programmes
using Cervarix. This feasibility
assessment will be performed
every 5 years.
vaccination against
anal lesions and
cancer.
against anal
lesions and
cancer
Status
(planned,
started)
Date for
submission of
interim or final
reports (planned
or actual)
Risk minimisation measures
Safety concern
Routine risk minimisation measures
Additional
risk
minimisation
measures
Theoretical risk of acquiring
vaccine-induced autoimmune
disease after vaccination
None
None
Use of HPV-16/18 vaccine in
HIV infected women or
subjects with known immune
deficiencies
Wording in SmPC (Warning and precautions)
None
Impact of HPV-16/18 vaccine
in women who are
inadvertently exposed to the
vaccine around pregnancy
onset or during pregnancy
Wording in SmPC (Pregnancy section)
“Except for asymptomatic human immunodeficiency virus
(HIV) infected subjects for whom limited data are available
(see “Pharmacodynamic Effects”); there are no data on the
use of Cervarix in subjects with impaired immune
responsiveness such as patients receiving
immunosuppressive treatment. As with other vaccines, an
adequate immune response may not be elicited in these
individuals.”
None
“Specific studies of the vaccine in pregnant women were not
conducted. Data in pregnant women collected as part of
pregnancy registries, epidemiological studies and inadvertent
exposure during clinical trials are insufficient to conclude
whether or not vaccination with Cervarix affects the risk of
adverse pregnancy outcomes including spontaneous abortion.
However, during the clinical development program, a total of
10,476 pregnancies were reported including 5,387 in women
who had received Cervarix. Overall, the proportions of
pregnant subjects who experienced specific outcomes (e.g.,
normal infant, abnormal infants including congenital
anomalies, premature birth, and spontaneous abortion) were
similar between treatment groups.
Animal studies do not indicate direct or indirect harmful
effects with respect to fertility, pregnancy, embryonal/foetal
development, parturition or post-natal development.
As a precautionary measure, it is preferable to avoid the use
of Cervarix during pregnancy. Women who are pregnant or
trying to become pregnant are advised to postpone or
interrupt vaccination until completion of pregnancy.”
HPV Type replacement
None
None
Impact and effectiveness
against anal lesions and
cancer
None
None
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2.7. Update of the Product information
As a consequence of this new indication, sections 4.1, 4.8, 5.1 of the SmPC have been updated. The
Package Leaflet has been updated accordingly.
Section 4.1 Therapeutic indications
Cervarix is a vaccine for use from the age of 9 years for the prevention of premalignant ano-genital
lesions (cervical, vulvar, and vaginal and anal) lesions and cervical and anal cancers causally related to
certain oncogenic Human Papillomavirus (HPV) types. See sections 4.4 and 5.1 for important
information on the data that support this indication. The use of Cervarix should be in accordance with
official recommendations.
Section 4.8 Undesirable effects
Summary of safety profile
In clinical studies that enrolled girls and women aged from 10 up to 72 years (of which 79.2% were
aged 10-25 years at the time of enrolment), Cervarix was administered to 16,142 subjects females
whilst 13,811 subjects females received control. These subjects were followed for serious adverse
events over the entire study period. In a pre-defined subset of subjects (Cervarix = 8,130 versus
control = 5,786), adverse events were followed for 30 days after each injection. In two clinical studies
that enrolled males aged 10 to 18 years, 2,617 males received Cervarix and were followed-up with
active safety surveillance.
(For the updated table of adverse reactions, please see attached PI)
Section 5.1 Pharmacodynamic properties (main changes)
Clinical studies
Immunogenicity in males aged 10 to 18 years
Immunogenicity in males was assessed in 2 clinical trials HPV-011 (N=173) and HPV-040 (N=556). The
data showed comparable immunogenicity in males and females. In study HPV-011, all subjects
seroconverted to both HPV-16 and 18 and GMT levels were non inferior to those observed in females
aged 15 to 25 years in study HPV-012.
Bridging of clinical efficacy against anal lesions and cancers
No efficacy study against anal premalignant lesions has been conducted with Cervarix. However, studies
conducted in girls aged 9 to 14 years (study HPV-071) and in women aged 18 to 45 years (study HPV010) have consistently shown a higher immune response with Cervarix than with the comparator for
which efficacy data against anal premalignant lesions are conclusive and have shown protection.
Changes were also made to the PI to bring it in line with the current Agency/QRD template and SmPC
guideline, which were reviewed by QRD and accepted by the CHMP.
2.7.1. User consultation
The Package Leaflet of Cervarix suspension for injection was subject to user testing at the time of the
Marketing authorisation Application (MAA), consistent with the obligations under Articles 59(3) and
61(1) of Directive 2001/83/EC (as amended by Directive 2004/27/EC). The Package Leaflet was tested
on clear comprehensibility (content) and clear legibility (format: font size, layout). The results of the
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user testing were submitted to the EMA during the review process of the MAA. The conclusion of the
report after the two rounds of testing was that the Package Leaflet was clear and legible.
According to Article 61(3) of Directive 2001/83/EC for changes to existing marketing authorisations, a
justification for not performing a full user consultation with target patient groups on the package
leaflet has been submitted by the MAH and has been found acceptable for the following reasons: this
variation does not contain major editorial changes to the package leaflet, and therefore it is agreed
with the MAH that the package leaflet is still legible, clear and easy to use. The CHMP agreed that no
new user testing should be provided.
3. Benefit-Risk Balance
Benefits
Beneficial effects
Cervarix has demonstrated clinical efficacy against cervical lesions and cancer associated with HPV
types 16 and 18 in females aged 15 years and older, and through immunogenicity bridging, vaccine
efficacy is inferred in the 9-14 year old female group.
Cervarix vaccination consistently shows sustained immunogenicity across age groups and according to
both licensed schedules. Immunogenicity of Cervarix has been compared to qHPV in studies HPV-010
and HPV-071 conducted in females 18-45 years of age and 9-14 years of age respectively. Noninferiority to qHPV was demonstrated for both study groups. Final results from study HPV-010 up to
Month 60 in females 18-45 years old who received 3-dose Cervarix showed that antibody titres remain
relatively stable over time after month 12 and superior to 3-dose qHPV regardless of baseline
serostatus (TVC cohort), across the three age strata. Superiority of the immune response elicited by
Cervarix administered according to the 2-dose schedule 0, 6 months compared to that of qHPV
administered according to the 2-dose 0, 6 months and the standard 3-dose 0, 2, 6 months schedules
was demonstrated for both HPV-16 and HPV-18 by ELISA up to Month 12 regardless of baseline
serostatus (TVC cohort) in HPV-071 study.
The data from studies HPV-011 and 040 in males subjects aged 10-18 and 12-15 years respectively
indicate comparable immunogenicity between males and females, when administered Cervarix
according to a 0, 1, 6-month schedule, irrespective of the pre-vaccination status of the subjects. Study
HPV-040 showed that comparable seroconversion rates (100%) and GMTs at Month 7 (24,000 vs.
21,000 for HPV16 and 8,500 vs. 8,100 for HPV18) are achieved in the ATP cohort after a 3-dose
Cervarix vaccination in males aged 12-15 years compared to females aged 12-15 years, for both HPV
16 and 18 types.
Another HPV vaccine (qHPV) was approved based on efficacy data against AIN 2/3 in the Men who
have sex with men (MSM, 16-26 years of age) and against intra-anal persistent infection related to
HPV16 and HPV18. Moreover, based on this clinical trial data, there is no evidence that efficacy of the
vaccine is gender specific and the estimates obtained in MSM would be applicable to women and
heterosexual men.
The issue whether or not AIN 2/3 lesions can be considered a surrogate marker for anal cancer is
resolved on the basis of the literature data available and also based on the striking similarities between
CIN and AIN as regards natural history, pathogenesis, histological appearance, spectrum of lesions and
high-risk HPV types. Overall these elements provide strong evidence that AIN 2/3 lesions are a
precursor of invasive HPV-related anal cancer and could be considered as a surrogate marker of
invasive anal cancer, in the same way as CIN 2/3 lesions are a surrogate marker for cervical cancer.
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In conclusion considering that the immune responses to Cervarix are consistently higher compared to
the approved comparator in the comparative studies available, the expected benefit from Cervarix
vaccination against anal lesions and cancers in a male and female population is considered acceptable
for licensure.
Uncertainty in the knowledge about the beneficial effects
No efficacy data were generated with Cervarix in the prevention of persistent anal infection, anal
lesions or anal cancer.
Published data following on from study HPV-009 data provide evidence of vaccine efficacy against anal
and cervical prevalent infection associated with HPV-16/18 and HPV-31/33/45 (Kreimer et al., Lancet
Oncology, 2011). The Kreimer data are obtained through a post-hoc study following the HPV-009
Costa Rica vaccine trial, of which the full data package is not available for assessment as it is
conducted by NCI. Kreimer et al. data showed efficacy of Cervarix against anal infection with HPV
types 16 and 18, which is the first necessary step of the pathogenic process for HPV-16/18 related
anal lesion and cancer, but the most relevant analyses on persistent anal infection are ongoing. Such
data should be submitted for review when available.
Further investigations of Cervarix efficacy against clinical efficacy endpoints (persistent infection, high
grade anal lesions and anal cancer) are not considered feasible.
The duration of protection against premalignant anal lesions and anal cancer is currently unknown. It
is considered to be the same as the duration of protection against cervical lesions, but the incidence of
anal cancer most likely peaks at a higher age. However, the cause of anal cancer, i.e. HPV infection, is
likely to occur within 5-20 years of vaccination in most cases and there is no reason to believe that the
acquisition pattern of HPV differs substantially between men and women. Considering that the immune
responses appear to decline slowly once a plateau value has been reached, the uncertainties regarding
duration of protection are now considered reduced compared to what was known previously.
The absolute benefit of protection against anal cancer may be limited at the population level, because
the incidence of anal cancer is low in the general population. However a substantial number of anal
cancer cases could be avoided in the general population and, more specifically, in the male population
by vaccinating individuals with Cervarix. There are uncertainties as to the magnitude of the increase of
incidence of anal cancer.
Risks
Unfavourable effects
The safety of Cervarix for administration in females is well documented through clinical trials and its
commercial use. The safety and reactogenicity assessment has therefore focused on the administration
of Cervarix in male subjects.
The safety results from the two studies HPV-011 and HPV-040 indicate that administration of Cervarix
is generally well tolerated in males 10 to 18 years of age. Overall, the safety profile in men is similar to
that in women and is in line with the currently approved SmPC.
The most common adverse reactions observed after vaccine administration was injection site pain.
These reactions were of mild to moderate severity and not long lasting.
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Uncertainty in the knowledge about the unfavourable effects
The exposure of Cervarix in males (2.617 males exposed to at least one dose) is limited at present.
Overall differences in the safety data between treatment groups or genders are not significant based
on descriptive comparative analysis.
The theoretical risk of acquiring an autoimmune disease following vaccination is raised by the
immunological action mechanism of vaccines. This important potential risk is identified for both males
and females although most autoimmune diseases disproportionally affect females. The RMP has been
updated to include this risk in males.
Benefit-Risk Balance
Importance of favourable and unfavourable effects
A large proportion of anal lesions and cancer cases are associated with HPV, predominantly types 16
and 18. Prophylactic vaccination against these oncogenic HPV types and as such prevention of the
disease represents a cornerstone among available medical approaches.
Cervarix consistently elicits sustained immunogenicity across age groups and according to both
licensed schedules. A multiple immunobridging strategy demonstrates non-inferior and superior
immune responses to the comparator in females of different age groups (from 9 to 45 years of age),
including those for which clinical efficacy against anal lesions was previously demonstrated with the
comparator. Comparative studies between genders show that Cervarix (3 dose schedule) elicits similar
immunogenicity in male vs female.
There is strong evidence that AIN 2/3 lesions are a precursor of invasive HPV-related anal cancer and
could be considered as a surrogate marker of invasive anal cancer, in the same way as CIN 2/3 lesions
are universally considered a surrogate marker for cervical cancer.
The safety profile of Cervarix is well characterised in females. Overall and based on clinical trial data in
men, the safety profile in men is similar to that in women and is in line with the currently approved
label.
Benefit-risk balance
Considering the inferred potential of Cervarix to prevent anal lesions and anal cancer in both males
and females, and the favourable safety profile, the benefit-risk balance is considered positive.
Discussion on the Benefit-Risk Balance
Although there is no immunological correlate of protection, it is believed and demonstrated in animal
models that protection against oncogenic HPV infection in humans is mainly based on the presence of
neutralizing antibodies as well as on cell-mediated immunity. Since the immune responses are
comparable between the two HPV vaccines Cervarix and qHPV, a vaccine approved for anal cancer
prevention, it is reasonable to conclude that Cervarix will confer an acceptable clinical protection
against premalignant anal lesions and cancer that is comparable with that of the approved vaccine.
The safety profile is similar in males vs. females and is considered favourable.
As a consequence, the Risk/Benefit profile for Cervarix remains favourable in the new indication for the
prevention of premalignant anal lesions and anal cancers causally related to certain oncogenic HPV
types.
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4. Recommendations
Outcome
Based on the review of the submitted data, the CHMP considers the following variation acceptable and
therefore recommends by majority of 29 out of 31 votes, the variation to the terms of the Marketing
Authorisation, concerning the following change:
Variation accepted
Type
C.I.6.a
Type II
Annexes
affected
C.I.6.a - Change(s) to therapeutic indication(s) - Addition
of a new therapeutic indication or modification of an
I, II, IIIA
and IIIB
approved one
Extension of Indication to include prevention against premalignant anal lesions and anal cancer as of 9
years of age for Cervarix; as a consequence, sections 4.1, 4.2, 4.3, 4.4, 4.5, 4.7, 4.8, 5.1 and 6.3 of
the SmPC are updated. The Package Leaflet and the RMP (final version 17.0) are updated in
accordance. In addition the MAH took the opportunity to implement QRD version 9.1 in the product
information.
The variation leads to amendments to the Summary of Product Characteristics, annex II, Labelling and
Package Leaflet and to the Risk Management Plan (RMP).
The divergent position to the majority recommendation is appended.
5. EPAR changes
The EPAR will be updated following Commission Decision for this variation. In particular the EPAR
module "steps after the authorisation" will be updated as follows:
Scope
Extension of Indication to include prevention against premalignant anal lesions and anal cancer as of 9
years of age for Cervarix; as a consequence, sections 4.1, 4.2, 4.3, 4.4, 4.5, 4.7, 4.8, 5.1 and 6.3 of
the SmPC are updated. The Package Leaflet and the RMP (final version 17.0) are updated in
accordance. In addition the MAH took the opportunity to implement QRD version 9.1 in the product
information
Summary
Please refer to the published Assessment Report Cervarix H-C-721-II-67-AR.
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APPENDIX
DIVERGENT POSITION
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Divergent position expressed by CHMP members:
The undersigned members of the CHMP did not agree with the CHMP’s positive opinion recommending
the variation to the terms of the marketing authorisation for the following reason(s):
An extension of the indication with premalignant anal lesions and anal cancer is not endorsed. Anal
cancer is a very uncommon cancer. Women have a higher incidence rate in age groups greater than 50
years but men dominate in the age ranges between 20 and 50 years old. In men and women, common
risk factors are e.g. receptive anal sex, lifetime number of sexual partners and genital warts.
Taking into consideration that the incidence of anal cancer in the overall population is very low, the
number of boys/adolescents prior to sexual debut to be vaccinated to prevent one case of anal
(pre)malignancy is considered too high, making the yield of population based vaccination most likely
extremely limited.
The benefit-risk balance of the proposed variation is considered negative.
London, 23 June 2016
………………………………………….
Pieter de Graeff
………………………………………….
Agnes Gyurasics
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